Encased Tamper Resistant Controlled Release Dosage Forms

ABSTRACT

In certain embodiments, the present invention is directed to a solid controlled release dosage form comprising: a core comprising a first portion of an opioid analgesic dispersed in a first matrix material; and a shell encasing the core and comprising a second portion of the opioid analgesic dispersed in a second matrix material; wherein the amount of opioid analgesic released from the dosage form is proportional within 20% to elapsed time from 8 to 24 hours, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 C.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/426,306 filed Dec. 22, 2010, the disclosure of which is incorporatedby reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to multi-layered pharmaceutical dosageforms that are tamper-resistant and preferably provide substantiallyzero-order release of the active agent contained therein.

BACKGROUND OF THE INVENTION

Pharmaceutical products are sometimes the subject of abuse. For example,a particular dose of opioid agonist may be more potent when administeredparenterally as compared to the same dose administered orally. Someformulations can be tampered with to provide the opioid agonistcontained therein for illicit use. Controlled release opioid agonistformulations are sometimes crushed or subject to extraction withsolvents (e.g., ethanol) by drug abusers to provide the opioid containedtherein for immediate release upon oral or parenteral administration.

Controlled release opioid agonist dosage forms that can liberate aportion of the opioid upon exposure to ethanol can also result in apatient receiving the dose more rapidly than intended if a patientdisregards instructions for use and concomitantly uses alcohol with thedosage form.

U.S. Patent Application Publication No. 2009/0081290 disclosestamper-resistant dosage forms that, in certain embodiments, are directedto a solid, oral, extended-release pharmaceutical dosage form comprisingan extended-release matrix formulation in the form of a tablet ormulti-particulates. The tablet or the individual multi-particulates canbe at least flattened without breaking, characterized by a thickness ofthe tablet or of the individual multi-particulates after flatteningwhich corresponds to no more than about 60% of the thickness of thetablet or the individual multi-particulates before flattening, andwherein the flattened tablet or the flattened multi-particulates providean in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C., having a percent amount of active released at 0.5 hoursof dissolution that deviates no more than about 20% points from thecorresponding in-vitro dissolution rate of a non-flattened referencetablet or reference multi-particulates.

There continues to exist a need in the art for tamper-resistantpharmaceutical oral dosage forms, wherein said dosage forms preferablyprovide a release profile of the active agent that is substantially zeroorder.

All references and publications cited herein are hereby incorporated byreference in their entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of certain embodiments of the present invention toprovide a solid controlled release dosage form comprising an activeagent (e.g., an opioid analgesic), which is tamper resistant.

It is an object of certain embodiments of the present invention toprovide a solid controlled release dosage form comprising an activeagent (e.g., an opioid analgesic), which is resistant to crushing.

It is an object of certain embodiments of the present invention toprovide a solid controlled release dosage form comprising an opioidanalgesic, which is subject to less parenteral abuse than other dosageforms.

It is an object of certain embodiments of the present invention toprovide a solid controlled release dosage form comprising an opioidanalgesic, which is subject to less intranasal abuse than other dosageforms.

It is an object of certain embodiments of the present invention toprovide a solid controlled release dosage form comprising an opioidanalgesic, which is subject to less oral abuse than other dosage forms.

It is a further object of certain embodiments of the present inventionto provide a solid controlled release dosage form comprising an opioidanalgesic, which is subject to less diversion than other dosage forms.

It is a further object of certain embodiments of the present inventionto provide a method of treating pain in human patients with a solidcontrolled release dosage form comprising an opioid analgesic whilereducing the abuse potential of the dosage form.

It is a further object of certain embodiments of the present inventionto treat a disease or condition (e.g., pain) by administering a solidcontrolled release dosage form as disclosed herein to a patient in needthereof.

It is a further object of certain embodiments of the present inventionto provide a method of manufacturing an oral dosage form of an activeagent (e.g., an opioid analgesic) as disclosed herein.

It is a further object of certain embodiments of the present inventionto provide a use of a medicament (e.g., an opioid analgesic) in themanufacture of a dosage form for the treatment of a disease state (e.g.,pain).

These objects and others are accomplished by the present invention,which in certain embodiments is directed to a solid controlled releasedosage form comprising a core comprising a first portion of an activeagent (e.g., an opioid analgesic) dispersed in a first matrix material;and a shell encasing the core and comprising a second portion of theactive agent dispersed in a second matrix material; wherein the amountof active agent released from the dosage form is proportional within 20%to elapsed time from 8 to 24 hours, as measured by an in-vitrodissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) at 37° C.

In certain other embodiments, the amount of active agent released fromthe dosage form is proportional within 30% to elapsed time in at leastone of (i) from 4 to 24 hours, (ii) from 8 to 24 hours, (iii) from 12 to24 hours, (iv) from 18 to 24 hours, (v) from 4 to 8 hours, (vi) from 4to 12 hours, (vii) from 4 to 18 hours, (viii) from 8 to 12 hours, (ix)from 8 to 18 hours, or (x) from 12 to 18 hours, as measured by anin-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C. In alternateembodiments, the amount of active agent released from the dosage form isproportional within 30% to elapsed time in all of (i) from 8 to 24hours, (ii) from 8 to 12 hours, and (iii) from 8 to 18 hours, asmeasured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain other embodiments, the amount of active agent released fromthe dosage form is proportional within 25% to elapsed time in at leastone of (i) from 4 to 24 hours, (ii) from 8 to 24 hours, (iii) from 12 to24 hours, (iv) from 18 to 24 hours, (v) from 4 to 8 hours, (vi) from 4to 12 hours, (vii) from 4 to 18 hours, (viii) from 8 to 12 hours, (ix)from 8 to 18 hours, or (x) from 12 to 18 hours, as measured by anin-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C. In alternateembodiments, the amount of active agent released from the dosage form isproportional within 25% to elapsed time in all of (i) from 8 to 24hours, (ii) from 8 to 12 hours, and (iii) from 8 to 18 hours, asmeasured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain other embodiments, the amount of active agent released fromthe dosage form is proportional within 20% to elapsed time in at leastone of (i) from 4 to 24 hours, (ii) from 8 to 24 hours, (iii) from 12 to24 hours, (iv) from 18 to 24 hours, (v) from 4 to 8 hours, (vi) from 4to 12 hours, (vii) from 4 to 18 hours, (viii) from 8 to 12 hours, (ix)from 8 to 18 hours, or (x) from 12 to 18 hours, as measured by anin-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C. In alternateembodiments, the amount of active agent released from the dosage form isproportional within 20% to elapsed time in all of (i) from 8 to 24hours, (ii) from 8 to 12 hours, and (iii) from 8 to 18 hours, asmeasured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain other embodiments, the amount of active agent released fromthe dosage form is proportional within 10% to elapsed time in at leastone of (i) from 4 to 24 hours, (ii) from 8 to 24 hours, (iii) from 12 to24 hours, (iv) from 18 to 24 hours, (v) from 4 to 8 hours, (vi) from 4to 12 hours, (vii) from 4 to 18 hours, (viii) from 8 to 12 hours, (ix)from 8 to 18 hours, or (x) from 12 to 18 hours, as measured by anin-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C. In alternateembodiments, the amount of active agent released from the dosage form isproportional within 10% to elapsed time in all of (i) from 8 to 24hours, (ii) from 8 to 12 hours, and (iii) from 8 to 18 hours, asmeasured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain other embodiments, the amount of active agent released fromthe dosage form is proportional within 5% to elapsed time in at leastone of (i) from 4 to 24 hours, (ii) from 8 to 24 hours, (iii) from 12 to24 hours, (iv) from 18 to 24 hours, (v) from 4 to 8 hours, (vi) from 4to 12 hours, (vii) from 4 to 18 hours, (viii) from 8 to 12 hours, (ix)from 8 to 18 hours, or (x) from 12 to 18 hours, as measured by anin-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C. In alternateembodiments, the amount of active agent released from the dosage form isproportional within 5% to elapsed time in all of (i) from 8 to 24 hours,(ii) from 8 to 12 hours, and (iii) from 8 to 18 hours, as measured by anin-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the present invention is directed to a solidcontrolled release dosage form comprising a core comprising a firstportion of an active agent (e.g., an opioid analgesic) dispersed in afirst matrix material comprising polyethylene oxide; and a shellencasing the core and comprising a second portion of the active agentdispersed in a second matrix material comprising polyethylene oxide. Inalternative embodiments, only the first matrix material comprisespolyethylene oxide or only the second matrix material comprisespolyethylene oxide.

In certain embodiments, the present invention is directed to a solidcontrolled release dosage form comprising a compressed core comprising afirst portion of an active agent (e.g., an opioid analgesic) dispersedin a first matrix material comprising polyethylene oxide; and acompression coating encasing the core and comprising a second portion ofthe active agent dispersed in a second matrix material comprisingpolyethylene oxide.

In certain embodiments, the present invention is directed to a solidcontrolled release dosage form comprising a core comprising a firstportion of an active agent (e.g., an opioid analgesic) dispersed in afirst matrix material; and a shell encasing the core and comprising asecond portion of the active agent dispersed in a second matrixmaterial; wherein the amount of active agent released from the dosageform at 2 hours is less than about 25%; the amount of active agentreleased from the dosage form at 4 hours is from about 10% to about 30%;the amount of active agent released from the dosage form at 8 hours isfrom about 20% to about 60%; the amount of active agent released fromthe dosage form at 12 hours is from about 40% to about 90%; and theamount of active agent released from the dosage form at 18 hours isgreater than about 70%; as measured by an in-vitro dissolution in a USPApparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) at 37° C.

In certain embodiments, the present invention is directed to a solidcontrolled release dosage form comprising a core comprising a firstportion of an active agent (e.g., an opioid analgesic) dispersed in afirst matrix material; and a shell encasing the core and comprising asecond portion of the active agent dispersed in a second matrixmaterial; wherein the amount of active agent released from the dosageform at 2 hours is less than about 20%; the amount of active agentreleased from the dosage form at 4 hours is from about 10% to about 30%;the amount of active agent released from the dosage form at 8 hours isfrom about 30% to about 60%; the amount of active agent released fromthe dosage form at 12 hours is from about 50% to about 90%; and theamount of active agent released from the dosage form at 18 hours isgreater than about 80%; as measured by an in-vitro dissolution in a USPApparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) at 37° C.

In certain embodiments, the present invention is directed to a solidcontrolled release dosage form comprising a core comprising a firstportion of an active agent (e.g., an opioid analgesic) dispersed in afirst matrix material; and a shell encasing the core and comprising asecond portion of the active agent dispersed in a second matrixmaterial; wherein the amount of active agent released from the dosageform at 2 hours is less than about 15%; the amount of active agentreleased from the dosage form at 4 hours is from about 8% to about 20%;the amount of active agent released from the dosage form at 8 hours isfrom about 20% to about 50%; the amount of active agent released fromthe dosage form at 12 hours is from about 40% to about 70%; the amountof active agent released from the dosage form at 18 hours is greaterthan about 70%; and the amount of active agent released from the dosageform at 24 hours is greater than about 90%; as measured by an in-vitrodissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) at 37° C. In certain embodiments,the present invention is directed to a solid controlled release dosageform comprising a therapeutically effective amount of hydrocodone or apharmaceutically acceptable salt thereof, and a controlled releaseexcipient; wherein the amount of opioid analgesic released from thedosage form is proportional within 20% to elapsed time from 8 to 24hours, as measured by an in-vitro dissolution in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C.; and the dosage form can be flattened without breaking,wherein the thickness of the dosage form after flattening corresponds tono more than about 20% of the thickness of the dosage form beforeflattening; and the amount of hydrocodone or salt thereof released at0.5 hour from a flattened dosage form deviates no more than about 20%points from a non-flattened dosage form as measured by an in-vitrodissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) at 37° C.

In certain embodiment, the present invention is directed to a solidcontrolled release dosage form comprising a therapeutically effectiveamount of hydrocodone or a pharmaceutically acceptable salt thereof, anda controlled release excipient; wherein the amount of hydrocodone orsalt thereof released from the dosage form at 2 hours is less than about25%; the amount of hydrocodone or salt thereof released from the dosageform at 4 hours is from about 10% to about 30%; the amount ofhydrocodone or salt thereof released from the dosage form at 8 hours isfrom about 20% to about 60%; the amount of hydrocodone or salt thereofreleased from the dosage form at 12 hours is from about 40% to about90%; and the amount of hydrocodone or salt thereof released from thedosage form at 18 hours is greater than about 70%; as measured by anin-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C.; and the dosageform can be flattened without breaking, wherein the thickness of thedosage form after flattening corresponds to no more than about 20% ofthe thickness of the dosage form before flattening; and the amount ofhydrocodone or salt thereof released at 0.5 hour from a flattened dosageform deviates no more than about 20% points from a non-flattened dosageform as measured by an in-vitro dissolution in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C.

In certain embodiments, the present invention is directed to a solidcontrolled release dosage form comprising a therapeutically effectiveamount of hydrocodone or a pharmaceutically acceptable salt thereofdispersed in a controlled release excipient; wherein the inner 60% ofthe dosage form contains at least 80% of the hydrocodone or saltthereof; wherein the amount of hydrocodone or salt thereof released fromthe dosage form is proportional within 20% to elapsed time from 8 to 24hours, as measured by an in-vitro dissolution in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C.

In certain embodiments, the present invention is directed to a method ofpreparing a solid controlled release dosage form comprising preparing acore comprising a first portion of an active agent (e.g., an opioidanalgesic) dispersed in a first matrix material; and encasing the corein a shell comprising a second portion of the active agent dispersed ina second matrix material; wherein the amount of active agent releasedfrom the dosage form is proportional within 20% to elapsed time from 8to 24 hours, as measured by an in-vitro dissolution in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C.

In certain embodiments, the present invention is directed to a method ofpreparing a solid controlled release dosage form comprising preparing acore comprising a first portion of an active agent (e.g., an opioidanalgesic) dispersed in a first matrix material comprising polyethyleneoxide; and encasing the core in a shell comprising a second portion ofthe active agent dispersed in a second matrix material comprisingpolyethylene oxide. In alternative embodiments, corresponding dosageforms are prepared such that only the first matrix material comprisespolyethylene oxide or only the second matrix material comprisespolyethylene oxide.

In certain embodiments, the present invention is directed to a method ofpreparing a solid controlled release dosage form comprising preparing acompressed core comprising a first portion of an active agent (e.g., anopioid analgesic) dispersed in a first matrix material comprisingpolyethylene oxide; and encasing the core by compression coating asecond portion of the active agent dispersed in a second matrix materialcomprising polyethylene oxide over the core. In alternative embodiments,corresponding compression coated dosage forms are prepared such thatonly the first matrix material comprises polyethylene oxide or only thesecond matrix material comprises polyethylene oxide.

In certain embodiments, the present invention is directed to a method ofpreparing a solid controlled release dosage form comprising preparing acore comprising a first portion of an active agent (e.g., an opioidanalgesic) dispersed in a first matrix material; and encasing the corein a shell comprising a second portion of the active agent dispersed ina second matrix material over the core; wherein the amount of activeagent released from the dosage form at 2 hours is less than about 25%;the amount of active agent released from the dosage form at 4 hours isfrom about 10% to about 30%; the amount of active agent released fromthe dosage form at 8 hours is from about 20% to about 60%; the amount ofactive agent released from the dosage form at 12 hours is from about 40%to about 90%; and the amount of active agent released from the dosageform at 18 hours is greater than about 70%, as measured by an in-vitrodissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the present invention is directed to a method ofpreparing a solid controlled release dosage form comprising combining atherapeutically effective amount of hydrocodone or a pharmaceuticallyacceptable salt thereof, and a controlled release excipient; wherein theamount of hydrocodone or salt thereof released from the dosage form at 2hours is less than about 25%; the amount of hydrocodone or salt thereofreleased from the dosage form at 4 hours is from about 10% to about 30%;the amount of hydrocodone or salt thereof released from the dosage format 8 hours is from about 20% to about 60%; the amount of hydrocodone orsalt thereof released from the dosage form at 12 hours is from about 40%to about 90%; and the amount of hydrocodone or salt thereof releasedfrom the dosage form at 18 hours is greater than about 70%; as measuredby an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in900 ml simulated gastric fluid without enzymes (SGF) at 37° C.; and thedosage form can be flattened without breaking, wherein the thickness ofthe dosage form after flattening corresponds to no more than about 20%of the thickness of the dosage form before flattening; and the amount ofhydrocodone or salt thereof released at 0.5 hour from a flattened dosageform deviates no more than about 20% points from a non-flattened dosageform as measured by an in-vitro dissolution in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C.

In certain embodiment, the present invention is directed to a method ofpreparing a solid controlled release dosage form comprising combining atherapeutically effective amount of hydrocodone or a pharmaceuticallyacceptable salt thereof, and a controlled release excipient; wherein theamount of hydrocodone or salt thereof released from the dosage form isproportional within 20% to elapsed time, at any two time points from 8to 24 hours, as measured by an in-vitro dissolution in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C.; and the dosage form can be flattened without breaking,wherein the thickness of the dosage form after flattening corresponds tono more than about 20% of the thickness of the dosage form beforeflattening; and the amount of hydrocodone or salt thereof released at0.5 hour from a flattened dosage form deviates no more than about 20%points from a non-flattened dosage form as measured by an in-vitrodissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the present invention is directed to a method ofpreparing a solid controlled release dosage form comprising dispersing atherapeutically effective amount of hydrocodone or a pharmaceuticallyacceptable salt thereof in a controlled release excipient; wherein theinner 60% of the dosage form contains at least 80% of the hydrocodone orsalt thereof; wherein the amount of hydrocodone or salt thereof releasedfrom the dosage form is proportional within 20% to elapsed time from 8to 24 hours, as measured by an in-vitro dissolution in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C.

In certain embodiments, the present invention is directed to a method oftreating pain in a patient or subject comprising administering a solidcontrolled release dosage form comprising an opioid analgesic asdisclosed herein.

In preferred embodiments, the present invention is directed to a dosageform of the present invention which exhibits a substantially zero-orderrelease rate after administration to a patient or subject.

The term “zero-order release rate” refers to the rate of active agentrelease from a dosage form which is independent of remaining activeagent concentration in the dosage form, such that the rate is relativelyconstant over a period of time. A dosage form exhibiting zero orderrelease rate would exhibit a relatively straight line in a graphicalrepresentation of percent active agent released versus time. In certainembodiments of the present invention, substantial zero order release isdefined as a dosage form having an amount of active agent released whichis proportional within 20% to elapsed time from 8 to 24 hours or 4 to 12hours, as measured by an in-vitro dissolution in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. For example, an amount released from a dosage formin-vitro at 8 hours of 20%, and an amount released at 24 hours of 60%(±12) would literally meet the definition of proportional within 20% toelapsed time from 8 to 24 hours. This is demonstrated by the latterelapsed time (24 hours) and the latter release (60%) being the samemultiple (3) of the former time (8 hours) and the former release (20%).To meet the definition of proportional within 20% to elapsed time from 8to 24 hours (or any other time period) it is only necessary to considerthe endpoints of the numerical values, although the definition does notpreclude that other time points within the endpoints may be proportionalas well.

In other embodiments of the present invention, substantial zero orderrelease is defined as a dosage form wherein the amount of active agentreleased at 2 hours is less than about 25%; the amount of active agentreleased from the dosage form at 4 hours is from about 10% to about 30%;the amount of active agent released from the dosage form at 8 hours isfrom about 20% to about 60%; the amount of active agent released fromthe dosage form at 12 hours is from about 40% to about 90%; and theamount of active agent released from the dosage form at 18 hours isgreater than about 70%; as measured by an in-vitro dissolution in a USPApparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) at 37° C.

The term “polyethylene oxide” is defined for purposes of the presentinvention as a composition of polyethylene oxide (PEO) having amolecular weight of at least 25,000, measured as is conventional in theart, and preferably having a molecular weight of at least 100,000.Compositions with lower molecular weight are usually referred to aspolyethylene glycols.

The term “high molecular weight polyethylene oxide (PEO)” is defined forproposes of the present invention as having an approximate molecularweight of at least 1,000,000, based on rheological measurements.

The term “low molecular weight polyethylene oxide (PEO)” is defined forpurposes of the present invention as having an approximate molecularweight of less than 1,000,000, based on rheological measurements.

The term “direct compression” is defined for purposes of the presentinvention as referring to a process wherein the dosage form is made by aprocess comprising the steps of blending the ingredients and compressingthe blend to form the dosage form, e.g., by using a diffusion blendand/or convection mixing process (e.g., Guidance for Industry,SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral DosageForms, Manufacturing Equipment Addendum).

The term “flattening” and related terms as used in the context offlattening a dosage form in accordance with the present invention meansthat the dosage form is subjected to force applied from a directionsubstantially in line with the smallest diameter (i.e., the thickness)of the dosage form when the shape is other than spherical, and from anydirection when the dosage form shape is spherical.

The term “resistant to crushing” is defined for the purposes of certainembodiments of the present invention as referring to dosage forms thatcan at least be flattened with a bench press as described herein withoutbreaking.

For purposes of the present invention, the term “opioid analgesic” meansone or more compounds selected from base opioid agonists, mixed opioidagonist-antagonists, partial opioid agonists, pharmaceuticallyacceptable salts, complexes, stereoisomers, ethers, esters, hydrates andsolvates thereof and mixtures thereof.

The term “simulated gastric fluid” or “SGF” used herein refers to anaqueous solution utilized in dissolution testing to mimic the conditionsof the stomach, e.g., a solution of 0.1 N HCl.

The term “percentage points” in the context of, e.g., “the amount ofactive agent released at 0.5 hour from a flattened dosage form deviatesno more than about 20% points from a non-flattened dosage form” meansthat the difference in the % release prior to flattening and the %release after flattening is no more than 20 (i.e., 20 or less). Forexample, 60% release from a flattened dosage form is no more than about20% points from the 40% release of a non-flattened dosage form.

The term “percentage” or the use of “%” without reference to “percentage(or %) points” is the ordinary meaning of percent. For example, 48%release is within 20% of 60% release, whereas 40% would not literally bewithin 20% of 60% release.

The term “patient” means a subject (preferably a human) who haspresented a clinical manifestation of a particular symptom or symptomssuggesting the need for treatment, who is treated preventatively orprophylactically for a condition, or who has been diagnosed with acondition to be treated.

The term “subject” is inclusive of the definition of the term “patient”and inclusive of the term “healthy subject” (i.e., an individual (e.g.,a human) who is entirely normal in all respects or with respect to aparticular condition.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposable on its mirror image and hence optically active whereinthe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of enantiomers.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

“Hydrocodone” is defined for purposes of the invention as includinghydrocodone free base, as well as pharmaceutically acceptable salts,complexes, stereoisomers, ethers, esters, hydrates and solvates thereofand mixtures thereof.

The term “USP Paddle or Basket Method” is the Paddle and Basket Methoddescribed, e.g., in U.S. Pharmacopoeia XII (1990).

The term “pH-dependent” for purposes of the present invention is definedas having characteristics (e.g., dissolution) which vary according toenvironmental pH.

The term “pH-independent” for purposes of the present invention isdefined as having characteristics (e.g., dissolution) which aresubstantially unaffected by pH.

The term “bioavailability” is defined for purposes of the presentinvention as the relevant extent to which the drug (e.g., hydrocodone)is absorbed from the unit dosage forms. Bioavailability is also referredto as AUC (i.e., area under the plasma concentration/time curve).

The term “controlled-release”, “extended-release” or “sustained release”are interchangeable and are defined for purposes of the presentinvention as the release of the drug (e.g., hydrocodone) at such a ratethat blood (e.g., plasma) concentrations are maintained within thetherapeutic range but below toxic concentrations over a period of timeof at least about 12 hours or longer, or at least 24 hours or longer.Preferably, a controlled release dosage form can provide once daily ortwice daily dosing.

The term “C_(max)” denotes the maximum plasma concentration obtainedduring the dosing interval.

The term “C₂₄” as it is used herein is the plasma concentration of thedrug at 24 hours after administration.

The term “T_(max)” denotes the time to maximum plasma concentration(C_(max)).

The term “C₂₄/C_(max) ratio” is defined for purposes of the presentinvention as the ratio of the plasma concentration of the drug at 24hours after administration to the highest plasma concentration of thedrug attained within the dosing interval.

The term “T_(lag)” denotes the time point immediately prior to the firstmeasurable plasma concentration.

The term “T_(1/2)” denotes the plasma half-life of the terminal phase.This is the time it takes for any concentration in the terminal phase todecrease by half. The term “minimum effective analgesic concentration”or “MEAC” with respect to concentrations of opioids such as hydrocodoneis very difficult to quantify. However, there is generally a minimallyeffective analgesic concentration of plasma hydrocodone below which noanalgesia is provided. While there is an indirect relationship between,e.g., plasma hydrocodone levels and analgesia, higher and prolongedplasma levels are generally associated with superior pain relief. Thereis a delay (or hysteresis) between the time of peak plasmahydrocodone-levels and the time of peak drug effects. This holds truefor the treatment of pain with opioid analgesics in general.

For purposes of the present invention, unless further specified, theterm “a patient” or “a subject” means that the discussion (or claim) isdirected to the pharmacokinetic parameters of an individual patient orsubject.

The term “population of patients” or “population of subjects” or“population of healthy subjects” means that the discussion (or claim) isdirected to the mean pharmacokinetic parameters of at least twopatients, subjects, or healthy subjects; at least six patients, subjectsor healthy subjects; or at least twelve patients, subjects or healthysubjects.

For purposes of the present invention, the controlled releaseformulations disclosed herein are preferably dose proportional. In doseproportional formulations, the pharmacokinetic parameters (e.g., AUC andC_(max)) and/or in-vitro release increase linearly from one dosagestrength to another. Therefore, the pharmacokinetic and in-vitroparameters of a particular dose can be inferred from the parameters of adifferent dose of the same formulation.

The term “first administration” means a single dose of the presentinvention at the initiation of therapy to an individual subject,patient, or healthy subject or a subject population, patient population,or healthy subject population.

The term “steady state” means that the amount of the drug reaching thesystem is approximately the same as the amount of the drug leaving thesystem. Thus, at “steady-state”, the patient's body eliminates the drugat approximately the same rate that the drug becomes available to thepatient's system through absorption into the blood stream.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph that depicts the dissolution of the compositions ofExamples 1-4.

FIG. 2 is a graph that depicts the dissolution of the compositions ofExamples 5 and 6.

FIG. 3 is a graph that depicts the dissolution of the compositions ofExamples 7-12.

FIG. 4 is a graph that depicts the mean plasma concentration time curveof Iteration 1 of Example 13.

FIG. 5 is a graph that depicts the mean plasma concentration time curveof Iteration 2 of Example 13.

FIG. 6 is a graph that depicts the mean plasma concentration time curveof Iteration 3 of Example 13.

FIG. 7 is a graph that depicts the plasma concentrations of thecompositions of Examples 14-20.

DETAILED DESCRIPTION

The present invention is directed to controlled release pharmaceuticalformulations that in certain embodiments comprise a higher concentrationof drug in an inner region of the dosage form as compared to an outerregion. Preferably, the inner and outer regions are configured as aninner core (e.g., a compressed tablet) and a shell encasing the core(e.g., a compression coating). The active agent can be contained solelyin the core or contained in both the core and the shell. In preferredembodiments, the release of the active agent from the dosage form issubstantially zero order, which provides dosing certainty and reducedplasma fluctuations as compared to alternative treatments (e.g.,immediate release dosage forms).

The dosage forms of the present invention are preferably tamperresistant as they are difficult to crush or grind (e.g., in accordancewith the flattening criteria disclosed herein). This characteristicmakes them especially suitable for controlled release opioid analgesicproducts that have a large dose of opioid analgesic intended to bereleased over a period of time from each dosage unit. Drug abuserstypically may take a controlled-release product and crush, shear, grind,chew, dissolve, heat, extract or otherwise damage the product so that alarge portion or the full contents of the dosage form becomes availablefor immediate absorption by injection, inhalation, and/or oralconsumption.

The shell of the dosage form of the present invention is preferablydifficult to physically separate from the core. This is particularlyuseful in embodiments that have an increased amount of active agent inthe core as compared to the shell, as abusers will have difficulty inaccessing the greater drug payload of the core.

In certain embodiments, the present invention is directed to a solidcontrolled release dosage form comprising: a core comprising a firstportion of an opioid analgesic dispersed in a first matrix material; anda shell encasing the core and comprising a second portion of the opioidanalgesic dispersed in a second matrix material.

The core of the dosage form can be formed, e.g., by direct compression,extrusion or molding. Preferably, the inner core provides a controlledrelease excipient and is in the form of a compressed tablet.

The shell of the dosage form can be formed, e.g., by compressioncoating, molding, spraying one or more layers onto the core, dipping oneor more layers onto the core or a combination thereof. Preferably, theshell contains a controlled release excipient and is a compressioncoating.

In preferred embodiments, the weight ratio of the core to the shell ofthe dosage forms described herein is from about 1:0.5 to about 1:5; fromabout 1:0.5 to about 1:2; from about 1:0.6 to about 1:1.5; or from about1:0.8 to about 1:1.2.

In preferred embodiments, the core and the shell are visuallyindistinguishable (e.g., by color) and there is not a clear demarcationbetween each component. This contributes to tamper resistance of thedosage form by hindering efforts to access the core, which in certainembodiments will contain the bulk of the active agent. One measurementthat can be utilized in order to evaluate the color of the shell and thecore is CIE L*A*B* value. Preferably, the CIE L*A*B* value of the coreand the shell are within 10% of each other. Another measurement toevaluate color is the use of a RYB or RGB color wheel, where the coreand shell preferably correspond to the same hue or adjacent hues.

In certain embodiments, the first matrix material comprises PEO. Inother embodiments, the second matrix material comprises PEO. In yetother embodiments, the first matrix material comprises PEO and thesecond matrix material comprises PEO. Preferably, polyethylene oxide iscontained in both components. In such embodiments, the molecular weightof the PEO in the first matrix material is the same or different thanthe average molecular weight in the second matrix material. In certainembodiments, molecular weight of the PEO contained in both components iswithin 20%, within 10% or within 5% of each other.

In preferred embodiments of the present invention, when polyethyleneoxide is present in both the first and second matrices, the molecularweight of the polyethylene oxide used in the first matrix (in the core)is lower than the molecular weight of the polyethylene oxide used in thesecond matrix material (in the shell). For example, in preferredembodiments, the polyethylene oxide in the first matrix material mayhave a molecular weight from about 300,000 to about 10,000,000 and thepolyethylene oxide in the second matrix material may have a molecularweight from about 1,000,000 to about 10,000,000. In other preferredembodiments, the polyethylene oxide in the first matrix material mayhave a molecular weight from about 300,000 to about 3,000,000 and thepolyethylene oxide in the second matrix material may have a molecularweight from about 4,000,000 to about 10,000,000. In other preferredembodiments, the polyethylene oxide in the first matrix material mayhave a molecular weight from about 500,000 to about 1,000,000 and thepolyethylene oxide in the second matrix material may have a molecularweight from about 6,000,000 to about 8,000,000.

In certain embodiments, the active agent (e.g., opioid analgesic) in thefirst portion (in the core) is the same as the active agent in thesecond portion (in the shell). In other embodiments, the active agent inthe first portion is different than the active agent in the secondportion.

In certain embodiments, the ratio of active agent (e.g., opioidanalgesic) in the core to the ratio of active agent in the shell is fromabout 1:1 to about 10:1; from about 2:1 to about 8:1; from about 2:1 toabout 5:1 or about 4:1.

In certain embodiments, the weight ratio of the first portion of activeagent (e.g., opioid analgesic) to polyethylene oxide in the first matrixmaterial is from about 1:0.25 to about 1:30; from about 1:0.5 to about1:100; from about 1:0.5 to about 1:20; from about 1:1 to about 1:10;from about 1:15 to about 1:20; from about 1:1.5 to about 1:4; about 1:18or about 1:2.

In alternative embodiments, the weight ratio of the second portion ofactive agent (e.g., opioid analgesic) to polyethylene oxide in thesecond matrix material is from about 1:1 to about 1:200; from about 1:1to about 1:125; from about 1:2 to about 1:100; from about 1:5 to about1:50; from about 1:12 to about 1:25; about 1:98 or about 1:15.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20%, orwithin 10%, or within 5% to elapsed time from 8 to 24 hours, as measuredby an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20%, orwithin 10%, or within 5% to elapsed time from 8 to 18 hours, as measuredby an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20%, orwithin 10%, or within 5% to elapsed time from 8 to 12 hours, as measuredby an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20%, orwithin 10%, or within 5% to elapsed time from 12 to 24 hours, asmeasured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20%, orwithin 10%, or within 5% to elapsed time from 12 to 18 hours, asmeasured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20%, orwithin 10%, or within 5% to elapsed time from 4 to 20 hours, as measuredby an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20%, orwithin 10%, or within 5% to elapsed time from 4 to 15 hours, as measuredby an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20%, orwithin 10%, or within 5% to elapsed time from 4 to 10 hours, as measuredby an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20%, orwithin 10%, or within 5% to elapsed time from 8 to 20 hours, as measuredby an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20%, orwithin 10%, or within 5% to elapsed time from 10 to 15 hours, asmeasured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released at 2 hours is less than about 25%; the amount ofactive agent released from the dosage form at 4 hours is from about 10%to about 30%; the amount of active agent released from the dosage format 8 hours is from about 20% to about 60%; the amount of active agentreleased from the dosage form at 12 hours is from about 40% to about90%; and the amount of active agent released from the dosage form at 18hours is greater than about 70%; as measured by an in-vitro dissolutionin a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastricfluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released at 2 hours is less than about 15%; the amount ofactive agent released from the dosage form at 4 hours is from about 10%to about 20%; the amount of active agent released from the dosage format 8 hours is from about 30% to about 45%; the amount of active agentreleased from the dosage form at 12 hours is from about 50% to about70%; and the amount of active agent released from the dosage form at 18hours is greater than about 90%; as measured by an in-vitro dissolutionin a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastricfluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released at 2 hours is less than about 10%; the amount ofactive agent released from the dosage form at 4 hours is from about 20%to about 30%; the amount of active agent released from the dosage format 8 hours is from about 45% to about 60%; the amount of active agentreleased from the dosage form at 12 hours is from about 70% to about90%; and the amount of active agent released from the dosage form at 18hours is greater than about 95%; as measured by an in-vitro dissolutionin a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastricfluid without enzymes (SGF) at 37° C.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20% toelapsed time from 8 to 24 hours, as measured by an in-vitro dissolutionin a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastricfluid without enzymes (SGF) at 37° C. and at least one of the followingis exhibited: (i) the amount of opioid analgesic released at 2 hours isless than about 20%, (ii) the amount of opioid analgesic released at 4hours is from about 10% to about 30%, (iii) the amount of opioidanalgesic released at 8 hours is from about 30% to about 60%, (iv) theamount of opioid analgesic released at 12 hours is from about 50% toabout 90%, or (v) the amount of opioid analgesic released at 18 hours isgreater than about 80%.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20% toelapsed time from 8 to 24 hours, as measured by an in-vitro dissolutionin a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastricfluid without enzymes (SGF) at 37° C. and at least one of the followingis exhibited: (i) the amount of opioid analgesic released at 2 hours isless than about 15%, (ii) the amount of opioid analgesic released at 4hours is from about 10% to about 20%, (iii) the amount of opioidanalgesic released at 8 hours is from about 30% to about 45%, (iv) theamount of opioid analgesic released at 12 hours is from about 50% toabout 70%, or (v) the amount of opioid analgesic released at 18 hours isgreater than about 90%.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20% toelapsed time from 8 to 24 hours, as measured by an in-vitro dissolutionin a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastricfluid without enzymes (SGF) at 37° C. and at least one of the followingis exhibited: (i) the amount of opioid analgesic released at 2 hours isless than about 10%, (ii) the amount of opioid analgesic released at 4hours is from about 20% to about 30%, (iii) the amount of opioidanalgesic released at 8 hours is from about 45% to about 60%, (iv) theamount of opioid analgesic released at 12 hours is from about 70% toabout 90%, or (v) the amount of opioid analgesic released at 18 hours isgreater than about 95%.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released from the dosage form is proportional within 20% toelapsed time from 8 to 24 hours, as measured by an in-vitro dissolutionin a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastricfluid without enzymes (SGF) at 37° C. and at least one of the followingis exhibited: (i) the amount of opioid analgesic released at 2 hours isless than about 15%, (ii) the amount of opioid analgesic released at 4hours is from about 8% to about 20%, (iii) the amount of opioidanalgesic released at 8 hours is from about 20% to about 50%, (iv) theamount of opioid analgesic released at 12 hours is from about 40% toabout 70%, (v) the amount of opioid analgesic released at 18 hours isgreater than about 70% or (vi) the amount of opiid analgesic releasedfrom the dosage form at 24 hours is greater than about 90%.

Dosage Forms

In certain embodiments, the core may be prepared by dry blending acontrolled release material, an active agent, and optionally otherexcipients, followed by granulating the mixture until proper granulationis obtained. The process can be performed by dry or wet granulationmethods. Typically with a wet granulation, the wet granules are dried ina fluid bed dryer, and sifted and ground to appropriate size.Lubricating agents are typically mixed with the granulation to obtainthe final core formulation.

A non-limiting list of suitable controlled release materials which maybe selected for inclusion in a formulation according to the presentinvention includes hydrophilic and hydrophobic materials such assustained release polymers, gums, acrylic resins, protein-derivedmaterials, waxes, shellacs, and oils such as hydrogenated castor oil andhydrogenated vegetable oil. More specifically, the controlled releasematerials can be, e.g., alkylcelluloses such as ethylcellulose, acrylicand methacrylic acid polymers and copolymers, and cellulose ethers, suchas hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) andcarboxyalkylcelluloses. Waxes include, e.g., natural and syntheticwaxes, fatty acids, fatty alcohols, and mixtures of the same (e.g.,beeswax, carnauba wax, stearic acid and stearyl alcohol). Certainembodiments utilize mixtures of two or more of the foregoing controlledrelease materials in the matrix of the core. However, anypharmaceutically acceptable hydrophobic or hydrophilic controlledrelease material which is capable of imparting controlled release of theactive agent may be used in accordance with the present invention.

The cores may also contain suitable quantities of additional excipients,e.g., lubricants, binders, granulating aids, diluents, colorants,flavorants (e.g., bittering agents) and glidants, all of which areconventional in the pharmaceutical art.

Specific examples of pharmaceutically acceptable diluents and excipientsthat may be used in formulating the cores are described in the Handbookof Pharmaceutical Excipients, American Pharmaceutical Association(1986), incorporated by reference herein.

In preferred embodiments, matrices of the dosage forms of the presentinvention incorporate polyethylene oxide (e.g., high and/or lowmolecular weight PEO).

Polyethylene oxide is considered to have an approximate molecular weightof 1,000,000 when a 2% (by wt) aqueous solution of the PEO using aBrookfield viscometer Model RVF, spindle No. 1, at 10 rpm, at 25° C.shows a viscosity range of 400 to 800 mPa-s (cP).

Polyethylene oxide is considered to have an approximate molecular weightof 2,000,000 when a 2% (by wt) aqueous solution of the PEO using aBrookfield viscometer Model RVF, spindle No. 3, at 10 rpm, at 25° C.shows a viscosity range of 2000 to 4000 mPa-s (cP).

Polyethylene oxide is considered to have an approximate molecular weightof 4,000,000 when a 1% (by wt) aqueous solution of the polyethyleneoxide using a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm,at 25° C. shows a viscosity range of 1650 to 5500 mPa-s (cP).

Polyethylene oxide is considered to have an approximate molecular weightof 5,000,000 when a 1% (by wt) aqueous solution of the polyethyleneoxide using a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm,at 25° C. shows a viscosity range of 5500 to 7500 mPa-s (cP).

Polyethylene oxide is considered to have an approximate molecular weightof 7,000,000 when a 1% (by wt) aqueous solution of the polyethyleneoxide using a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm,at 25° C. shows a viscosity range of 7500 to 10,000 mPa-s (cP).

Polyethylene oxide is considered to have an approximate molecular weightof 8,000,000 when a 1% (by wt) aqueous solution of the polyethyleneoxide using a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm,at 25° C. shows a viscosity range of 10,000 to 15,000 mPa-s (cP).

Regarding the lower molecular weight polyethylene oxides, polyethyleneoxide is considered to have an approximate molecular weight of 100,000when a 5% (by wt) aqueous solution of the polyethylene oxide using aBrookfield viscometer Model RVT, spindle No. 1, at 50 rpm, at 25° C.shows a viscosity range of 30 to 50 mPa-s (cP).

Polyethylene oxide is considered to have an approximate molecular weightof 900,000 when a 5% (by wt) aqueous solution of the polyethylene oxideusing a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25°C. shows a viscosity range of 8800 to 17,600 mPa-s (cP).

Compression Coated Dosage Forms

In embodiments utilizing compression coating, it is preferred that allor part of the pharmaceutically acceptable excipient(s) in the coatingshould impart sufficient compressibility to provide a pharmaceuticallyacceptable product. The compression coating onto the pre-formed core isdependent in part on the individual characteristics of the selectedexcipients and the active agent, e.g., in terms of polymer solubility,flowability, glass transition temperature, etc.

Compression coated dosage forms can be prepared, e.g., by utilizing apre-manufactured core or preparing a core (e.g., by compression) priorto the coating. The inner core can be prepared by wet or dry granulatingactive agent together with the pharmaceutically acceptable excipients;followed by drying and milling as necessary to obtain a granulate;adding optional extragranular excipients and/or active agent withappropriate blending; adding a lubricant as needed; and compressing thegranulate with a tablet press. The resultant compressed core can beoptionally coated with a functional coating or film coating prior tocompression coating.

The blend for compression coating can be prepared by a similar processas the blend for the core utilizing any of the controlled releasematerials disclosed above. Preferably, the compression coating includespolyethylene oxide. The blend can be coated onto the core bycompression. The compression of the core and/or the coating can utilizea Killion or Fette rotary press at a compression force, e.g., from about1 to about 20 kilonewtons.

In certain embodiments, a Manesty Dry-Cota press (e.g., Model 900) canbe utilized. This apparatus consists of two side by side interconnectedtablet presses where the core is made on one press and then mechanicallytransferred to the next press for compression coating. Each press has anindependent powder feed mechanism so that the core blend is loaded onone machine, and the coating blend is loaded on the other machine.Mechanical transfer arms rotate between the machines to remove coresfrom the core press and transfer them to the coating press. Otherpresses which may be used to prepare the dosage forms of the presentinvention include Elizabeth Hata HT-AP44-MSU-C; Killian RLUD; and FettePT 4090, each of which has a dual feed system for coating blend andpre-made cores. Utilizing these presses allows multiple compressioncoating-layers to be achieved by recycling tablets that have alreadybeen compression-coated. All of these presses have mechanisms to centerthe tablet within the coating blend both vertically and radially.

In certain embodiments, the compression coating is not applied at thesame thickness at all points around the inner core, but instead isapplied at different thicknesses around the inner core. Thinner areas ofcoating will produce areas of the compressed dosage form that willrelease drug from the inner core sooner than other areas. This may besimply accomplished, e.g., by having the core to which the compressioncoating is being applied not being centered in the press at the time ofcoating.

In certain embodiments, the compression coated dosage form can befurther overcoated with a hydrophobic or enteric coating material. Inother embodiments, the compression coated dosage forms can be coatedwith a hydrophilic coating in addition to or instead of the hydrophobicor enteric coating.

In still further embodiments, an optional coat (e.g., hydrophobic,hydrophilic or enteric) may be alternatively or additionally applied asan intermediate layer between the core and the compression coating.

Active Agents

Opioid analgesics useful in the present invention include, but are notlimited to, alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propoxyphene, sufentanil, tilidine, tramadol,pharmaceutically acceptable salts, complexes (e.g., with acyclodextrin), stereoisomers, ethers, esters, hydrates, solvates, andmixtures thereof.

Preferably, the opioid analgesic is selected from the group consistingof codeine, hydrocodone, hydromorphone, morphine, oxycodone,oxymorphone, tramadol, pharmaceutically acceptable salts, complexes,stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.

In certain embodiments, the opioid analgesic is selected from the groupconsisting of hydrocodone, pharmaceutically acceptable salts, complexes,stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.Preferably, the opioid analgesic is hydrocodone bitartrate.

The opioids used according to the present invention may contain one ormore asymmetric centers and may give rise to enantiomers, diastereomers,or other stereoisomeric forms. The present invention is meant toencompass the use of all such possible forms as well as their racemicand resolved forms and compositions thereof. When the compoundsdescribed herein contain olefinic double bonds or other centers ofgeometric asymmetry, it is intended to include both E and Z geometricisomers. All tautomers are intended to be encompassed by the presentinvention as well.

Pharmaceutically acceptable salts include, but are not limited to,inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparaginate, glutamate and the like;metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; and organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like.

Additionally, active agents other than opioid analgesics that arepotentially subject to abuse may be used in accordance with the presentinvention. Such agents include, e.g., tranquilizers, CNS depressants,CNS stimulants, sedatives, hypnotics, stimulants (including appetitesuppressants such as phenylpropanolamine), and cannabinoids, amongothers. More specifically, the active agent can be selected frombarbiturates such as phenobarbital, secobarbital, pentobarbital,butabarbital, talbutal, aprobarbital, mephobarbital, butalbital,pharmaceutically acceptable salts thereof, and the like; benzodiazepinessuch as diazepam, chlordiazepoxide, alprazolam, triazolam, estazolam,clonazepam, flunitrazepam, pharmaceutically acceptable salts thereof,and the like; stimulants such as gamma-hydroxybutyrate,dextroamphetamine, methylphenidate, sibutramine,methylenedioxyrnethamphetamine, pharmaceutically acceptable saltsthereof, and the like; other agents such as marinol, meprobamate andcarisoprodol; and all pharmaceutically acceptable salts, complexes,stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.

In further embodiments, other therapeutically active agents may be usedin accordance with the present invention, either alone or in combinationwith opioids. Examples of such therapeutically active agents includeantihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramineand dexchlorpheniramine maleate), non-steroidal anti-inflammatory agents(e.g., naproxen, diclofenac, indomethacin, ibuprofen, sulindac, Cox-2inhibitors), acetaminophen, anti-emetics (e.g., metoclopramide,methylnaltrexone), anti-epileptics (e.g., phenyloin, meprobmate andnitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem andnicardipine), anti-tussive agents and expectorants, anti-asthmatics(e.g. theophylline), antacids, anti-spasmodics (e.g., atropine,scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynicacid, bendrofluthiazide), anti-hypotensives (e.g., propranolol,clonidine), antihypertensives (e.g., clonidine, methyldopa),bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone,triamcinolone, prednisone), antibiotics (e.g., tetracycline),anti-hemorrhoidals, psychotropics, anti-diarrheals, mucolytics,decongestants (e.g., pseudoephedrine), laxatives, vitamins, and thepharmaceutically acceptable salts, complexes, stereoisomers, ethers,esters, hydrates, solvates, and mixtures thereof.

Hydrocodone Embodiments

The controlled release oral dosage forms of the present inventionpreferably include from about 0.5 mg to about 1250 mg hydrocodone or anequivalent amount of a pharmaceutically acceptable salt thereof. Inother embodiments, the dosage forms contain from about 2 mg to about 200mg hydrocodone or an equivalent amount of a pharmaceutically acceptablesalt thereof, or from about 16 mg to about 120 mg hydrocodone or anequivalent amount of a pharmaceutically acceptable salt thereof. Incertain preferred embodiments, the dosage form contains about 20 mg,about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg orabout 120 mg hydrocodone bitartrate.

Suitable pharmaceutically acceptable salts of hydrocodone includehydrocodone bitartrate, hydrocodone bitartrate hydrate, hydrocodonehydrochloride, hydrocodone p-toluenesulfonate, hydrocodone phosphate,hydrocodone thiosemicarbazone, hydrocodone sulfate, hydrocodonetrifluoroacetate, hydrocodone hemipentahydrate, hydrocodonepentafluoropropionate, hydrocodone p-nitrophenylhydrazone, hydrocodoneo-methyloxime, hydrocodone semicarbazone, hydrocodone hydrobromide,hydrocodone mucate, hydrocodone oleate, hydrocodone phosphate dibasic,hydrocodone phosphate monobasic, hydrocodone inorganic salt, hydrocodoneorganic salt, hydrocodone acetate trihydrate, hydrocodonebis(heptafluorobutyrate), hydrocodone bis(methylcarbamate), hydrocodonebis(pentafluoropropionate), hydrocodone bis(pyridine carboxylate),hydrocodone bis(trifluoroacetate), hydrocodone chlorhydrate, andhydrocodone sulfate pentahydrate. Preferably, the hydrocodone is presentas the bitartrate salt.

A hydrocodone dosage form of the present invention may further includeone or more additional drugs, which may or may not act synergisticallywith the hydrocodone contained therein. Examples of such additionaldrugs include non-steroidal anti-inflammatory agents, includingibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam, isoxicam and the pharmaceutically acceptable salts,complexes, stereoisomers, ethers, esters, hydrates, solvates, andmixtures thereof. Such non-steroidal anti-inflammatory agents alsoinclude cyclo-oxygenase inhibitors such as celecoxib, meloxicam,nabumetone, nimesulide and the pharmaceutically acceptable salts,complexes, stereoisomers, ethers, esters, hydrates, solvates, andmixtures thereof.

Other additional drugs that can be co-formulated with hydrocodoneinclude NMDA receptor antagonists such as dextrorphan, dextromethorphan,3-(1-naphthalennyl)-5-(phosphonomethyl)-L-phenylalanine,3-(1-naphthalenyl)-5-(phosphonomethyl)-DL-phenylalanine,1-(3,5-dimethylphenyl)naphthalene, 2-(3,5-dimethylphenyl) naphthalene,2SR,4RS-4-(((1H-Tetrazol-5-yl)methyl)oxy)piperidine-2-carboxylic acid,2SR,4RS-4-((((1H-Tetrazol-5-yl)methyl)oxy)methyl)piperidine-2-carboxylicacid, E and Z2SR-4-(O-(1H-Tetrazol-5-yl)methyl)ketoximino)piperidine-2-carboxylicacid, 2SR,4RS-4-((1H-Tetrazol-5-yl)thio)piperidine-2-carboxylic acid,2SR,4RS-4-((1H-Tetrazol-5-yl)thio)piperidine-2-carboxylic acid,2SR,4RS-4-(5-mercapto-1H-Tetrazol-1-yl)piperidine-2-carboxylic acid,2SR,4RS-4-(5-mercapto-2H-Tetrazol-2-yl)piperidine-2-carboxylic acid,2SR,4RS-4-(5-mercapto-1H-Tetrazol-1-yl)piperidine-2-carboxylic acid,2SR,4RS-4-(5-mercapto-2H-Tetrazol-2-yl)piperidine-2-carboxylic acid,2SR,4RS-4-(((1H-Tetrazol-5-yl)thio)methyl)piperidine-2-carboxylic acid,2SR,4RS-4-((5-mercapto-1H-Tetrazol-1-yl)methyl)piperidine-2-carboxylicacid,2SR,4RS-4-((5-mercapto-2H-Tetrazol-2-yl)methyl)piperidine-2-carboxylicacid, and the pharmaceutically acceptable salts, complexes,stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.

Other suitable drugs which may be included in the hydrocodone dosageforms of the present invention include acetaminophen and aspirin.

In preferred embodiments, the hydrocodone formulations of the presentinvention are suitable for once-a-day administration and provide arelatively flat plasma profile, meaning that the plasma level of thehydrocodone provides a C₂₄/C_(max) ratio of about 0.55 to about 1.0after administration. In certain embodiments, the C₂₄/C_(max) ratio isabout 0.55 to about 0.85, about 0.55 to about 0.75 or about 0.60 toabout 0.70 after administration of the dosage form.

In preferred embodiments, the hydrocodone formulations of the presentinvention provide a T_(max) (h) of hydrocodone from about 4 to about 20hours after administration. In certain embodiments, the T_(max) is about6 to about 12 hours, about 8 to about 10 hours, about 4 to about 10hours, about 8 to about 14 hours, or about 14 to about 20 hours afteradministration of the dosage form.

In still other embodiments, a solid controlled release dosage form ofthe present invention provides an AUC (ng*h/mL) after administration ofabout 200 to 450 or about 250 to 400 per each 20 mg hydrocodone orpharmaceutically acceptable salt thereof included in the dosage form.

In certain embodiments, a solid controlled release dosage form thatcontains 20 mg hydrocodone or a pharmaceutically acceptable salt thereofprovides an AUC (ng*h/mL) after administration of about 200 to about450, about 250 to about 400, about 275 to about 350, about 300 to 330 orabout 280 to about 320.

In certain embodiments, a solid controlled release dosage form thatcontains 120 mg hydrocodone or a pharmaceutically acceptable saltthereof provides an AUC (ng*h/mL) after administration of about 1000 toabout 3000, about 1500 to about 2400, about 1700 to about 2200, about1800 to about 2100 or about 1900 to about 2100.

In other embodiments, a solid controlled release dosage form of thepresent invention provides a C. (ng/mL) after administration of about 5to about 40, about 10 to about 30 per each 20 mg hydrocodone included inthe dosage form.

In certain embodiments, a solid controlled release dosage form thatcontains 20 mg hydrocodone or a pharmaceutically acceptable salt thereofprovides a C_(max) (ng/mL) after administration of about 5 to about 40,about 10 to about 30, about 12 to about 25, about 14 to about 18 orabout 12 to about 17.

In certain embodiments, a solid controlled release dosage form thatcontains 120 mg hydrocodone or a pharmaceutically acceptable saltthereof provides a C_(max) (ng/mL) after administration of about 30 toabout 120, about 60 to about 180, about 100 to about 160, about 110 toabout 150 or about 100 to about 140.

In certain embodiments, a solid controlled release dosage form of thepresent invention provides a T_(max) (h) of hydrocodone afteradministration of about 7 to about 22, 10 to about 20, about 12 to about18, about 13 to about 17 or about 14 to about 16.

In other embodiments, a solid controlled release dosage form of thepresent invention provides a T_(1/2) (h) of hydrocodone afteradministration of about 5 to about 10, about 6 to about 9, about 7 orabout 8.

In other embodiments, a solid controlled release dosage form of thepresent invention provides a T_(lag) (h) of hydrocodone afteradministration of about 0.01 to about 0.2, about 0.1 to about 0.18,about 0.3 to about 0.17 or about 0.06 t about 0.15.

In other embodiments, a solid controlled release dosage form of thepresent invention provides a C₂₄/C_(max) ratio of hydrocodone of about0.2 to about 0.8, about 0.3 to about 0.7 or about 0.4 to about 0.6.

In certain embodiments, any one or all of the above mean in vivoparameters are achieved after administration in the fasted state.

In certain embodiments, the mean AUC (ng*h/mL) of hydrocodone afteradministration in the fed state is less than 20% higher, less than 16%higher or less than 12% higher than the AUC (ng*h/mL) of hydrocodoneafter administration in the fasted state.

In certain embodiments, the mean C_(max) (ng/mL) of hydrocodone afteradministration in the fed state is less than 80% higher, less than 70%higher or less than 60% higher than the C_(max) of hydrocodone afteradministration in the fasted state.

In certain embodiments, the mean T_(max) (h) of hydrocodone afteradministration in the fed state is within 25%, within 20% or within 15%of the T_(max) of hydrocodone after administration in the fasted state.

In certain embodiments, the mean T_(1/2) (h) of hydrocodone afteradministration in the fed state is within 8%, within 5% or within 2% ofthe T_(1/2) after administration in the fasted state.

In certain embodiments, the mean T_(lag) of hydrocodone afteradministration in the fed state is less than 150% higher, less than 125%higher or less than 100% higher than the T_(1/2) after administration inthe fasted state.

In certain embodiments, any one or all of the above in vivo parametersare achieved after a first administration of the dosage form to a humansubject, patient, or healthy subject (individual data) or a populationof human subjects, patients or healthy subjects (mean data).

In certain alternative embodiments, any one or all of the above in vivoparameters are achieved after steady state administration of the dosageform to a human subject, patient or healthy subject or a population ofhuman subjects, patients or healthy subjects.

Cured Formulations

In certain embodiments, a process of the present invention furthercomprises the step of curing the final dosage form.

For embodiments comprising polyethylene oxide in a controlled releaseformulation, the curing step may comprise at least partially melting thepolyethylene oxide in the formulation. In certain embodiments, at leastabout 20% or at least about 30% of the polyethylene oxide in theformulation melts. Preferably, at least about 40%, or at least about50%, or at least about 60%, or at least about 75%, or at least about 90%of the polyethylene oxide in the formulation melts during the curingstep. In a preferred embodiment, about 100% of the polyethylene oxidemelts.

In other embodiments, the curing step comprises subjecting theformulation to an elevated temperature for a certain period of time. Insuch embodiments, the curing temperature is at least as high as thesoftening temperature of the polyethylene oxide. According to certainembodiments, the curing temperature is at least about 60° C., at leastabout 62° C., ranges from about 62° C. to about 90° C., from about 62°C. to about 85° C., from about 62° C. to about 80° C., from about 65° C.to about 90° C., from about 65° C. to about 85° C., or from about 65° C.to about 80° C. The curing temperature preferably ranges from about 68°C. to about 90° C., from about 68° C. to about 85° C., from about 68° C.to about 80° C., from about 70° C. to about 90° C., from about 70° C. toabout 85° C., from about 70° C. to about 80° C., from about 72° C. toabout 90° C., from about 72° C. to about 85° C. or from about 72° C. toabout 80° C. The curing temperature may be at least about 60° C., atleast about 62° C., less than about 90° C. or less than about 80° C.Preferably, it is in the range of from about 62° C. to about 72° C. orfrom about 68° C. to about 72° C. Preferably, the curing temperature isat least as high as the lower limit of the softening temperature rangeof the polyethylene oxide, or at least about 62° C., or at least about68° C. More preferably, the curing temperature is within the softeningtemperature range of the polyethylene oxide, or at least about 70° C. Infurther embodiments, the curing temperature is at least as high as theupper limit of the softening temperature range of the polyethyleneoxide, or at least about 72° C. In further embodiments, the curingtemperature is higher than the upper limit of the softening temperaturerange of the polyethylene oxide, or at least about 75° C., or at leastabout 80° C.

In those embodiments where the curing step involves subjecting theformulation to an elevated temperature for a certain period of time,this period of time is hereinafter referred to as the curing time. Forthe measurement of the curing time, a starting point and an end point ofthe curing step are defined. For the purposes of the present invention,the starting point of the curing step is defined to be the point in timewhen the curing temperature is reached.

In certain embodiments, the temperature profile during the curing stepshows a plateau-like form between the starting point and the end pointof the curing. In such embodiments, the end point of the curing step isdefined to be the point in time when the heating is stopped or at leastreduced, e.g. by terminating or reducing the heating and/or by startinga subsequent cooling step, and the temperature subsequently drops belowthe curing temperature by more than about 10° C. and/or below the lowerlimit of the softening temperature range of polyethylene oxide, forexample, below about 62° C. When the curing temperature is reached andthe curing step is thus started, deviations from the curing temperaturein the course of the curing step can occur. Such deviations aretolerated as long as they do not exceed a value of about ±10° C.,preferably about ±6° C., and more preferably about ±3° C. For example,if a curing temperature of at least about 75° C. is to be maintained,the measured temperature may temporarily increase to a value of about85° C., about 81° C., or about 78° C., and the measured temperature mayalso temporarily drop down to a value of about 65° C., about 69° C. orabout 72° C. In the cases of a larger decrease of the temperature and/orin the case that the temperature drops below the lower limit of thesoftening temperature range of polyethylene oxide, for example belowabout 62° C., the curing step is discontinued, i.e. an end point isreached. Curing can be restarted by again reaching the curingtemperature.

In other embodiments, the temperature profile during the curing stepshows a parabolic or triangular form between the starting point and theend point of the curing. This means that after the starting point, i.e.,the point in time when the curing temperature is reached, thetemperature further increases to reach a maximum, and then decreases. Insuch embodiments, the end point of the curing step is defined to be thepoint in time when the temperature drops below the curing temperature.

Depending on the apparatus used for the curing (i.e., curing device),different temperatures within the curing device can be measured tocharacterize the curing temperature.

In certain embodiments, the curing step may take place in an oven. Insuch embodiments, the temperature inside the oven is measured. Basedthereon, when the curing step takes place in an oven, the curingtemperature is defined to be the target inside temperature of the ovenand the starting point of the curing step is defined to be the point intime when the inside temperature of the oven reaches the curingtemperature. The end point of the curing step is defined to be (1) thepoint in time when the heating is stopped or at least reduced and thetemperature inside the oven subsequently drops below the curingtemperature by more than about 10° C. and/or below the lower limit ofthe softening temperature range of high molecular weight polyethyleneoxide, for example below about 62° C., in a plateau-like temperatureprofile or (2) the point in time when the temperature inside the ovendrops below the curing temperature in a parabolic or triangulartemperature profile. Preferably, the curing step starts when thetemperature inside the oven reaches a curing temperature of at leastabout 62° C., at least about 68° C., at least about 70° C., at leastabout 72° C. or at least about 75° C. In preferred embodiments, thetemperature profile during the curing step shows a plateau-like form,wherein the curing temperature, i.e. the inside temperature of the oven,is at least about 68° C., about 70° C., about 72° C., about 73° C., orlies within a range of from about 70° C. to about 75° C., and the curingtime is preferably in the range of from about 30 minutes to about 20hours, from about 30 minutes to about 15 hours, from about 30 minutes toabout 4 hours, or from about 30 minutes to about 2 hours. In certainembodiments, the curing time is in the range of from about 30 minutes toabout 90 minutes.

In certain other embodiments, the curing takes place in curing devicesthat are heated by an air flow and comprise a heated air supply (inlet)and an exhaust, e.g., a coating pan or fluidized bed. Such curingdevices will hereinafter be called convection curing devices. In suchcuring devices, it is possible to measure the temperature of the inletair, i.e., the temperature of the heated air entering the convectioncuring device and/or the temperature of the exhaust air, i.e., thetemperature of the air leaving the convection curing device. It is alsopossible to determine or at least estimate the temperature of theformulations inside the convection curing device during the curing step,e.g., by using infrared temperature measurement instruments (such as anIR gun) or by measuring the temperature using a temperature probe thatwas placed inside the curing device near the formulations. Basedthereon, when the curing step takes place in a convection curing device,the curing temperature can be defined and the curing time can bemeasured as follows.

In one embodiment (method 1), the curing temperature is defined to bethe target inlet air temperature and the starting point of the curingstep is defined to be the point in time when the inlet air temperaturereaches the curing temperature. The end point of the curing step isdefined to be (1) the point in time when the heating is stopped or atleast reduced and the inlet air temperature subsequently drops below thecuring temperature by more than about 10° C. and/or below the lowerlimit of the softening temperature range of high molecular weightpolyethylene oxide, for example below about 62° C., in a plateau-liketemperature profile, or (2) the point in time when the inlet airtemperature drops below the curing temperature in a parabolic ortriangular temperature profile. Preferably, the curing step startsaccording to method 1, when the inlet air temperature reaches a curingtemperature of at least about 62° C., at least about 68° C., at leastabout 70° C., at least about 72° C. or at least about 75° C. In apreferred embodiment, the temperature profile during the curing stepshows a plateau-like form, wherein the curing temperature, i.e. thetarget inlet air temperature, is preferably at least about 72° C., forexample, about 75° C., and the curing time which is measured accordingto method 1 is preferably in the range of from about 15 minutes to about2 hours, for example, about 30 minutes or about 1 hour.

In another embodiment (method 2), the curing temperature is defined tobe the target exhaust air temperature, and the starting point of thecuring step is defined to be the point in time when the exhaust airtemperature reaches the curing temperature. The end point of the curingstep is defined to be (1) the point in time when the heating is stoppedor at least reduced and the exhaust air temperature subsequently dropsbelow the curing temperature by more than about 10° C. and/or below thelower limit of the softening temperature range of high molecular weightpolyethylene oxide, for example below about 62° C., in a plateau-liketemperature profile, or (2) the point in time when the exhaust airtemperature drops below the curing temperature in a parabolic ortriangular temperature profile. Preferably, the curing step startsaccording to method 2, when the exhaust air temperature reaches a curingtemperature of at least about 62° C., at least about 68° C., at leastabout 70° C., at least about 72° C. or at least about 75° C. Inpreferred embodiments, the temperature profile during the curing stepshows a plateau-like form, wherein the curing temperature, i.e. thetarget exhaust air temperature, is preferably at least about 68° C., atleast about 70° C. or at least about 72° C., for example the targetexhaust air temperature is about 68° C., about 70° C., about 72° C.,about 75° C. or about 78° C., and the curing time which is measuredaccording to method 2 is preferably in the range of from about 1 minuteto about 2 hours or from about 5 minutes to about 90 minutes, forexample, the curing time is about 5 minutes, about 10 minutes, about 15minutes, about 30 minutes, about 60 minutes, about 70 minutes, about 75minutes or about 90 minutes. In a more preferred embodiment, the curingtime which is measured according to method 2 is in the range of fromabout 15 minutes to about 1 hour.

In a further embodiment (method 3), the curing temperature is defined tobe the target temperature of the formulations and the starting point ofthe curing step is defined to be the point in time when the temperatureof the formulations, which can be measured for example by an IR gun,reaches the curing temperature. The end point of the curing step isdefined to be (1) the point in time when the heating is stopped or atleast reduced and the temperature of the formulations subsequently dropsbelow the curing temperature by more than about 10° C. and/or below thelower limit of the softening temperature range of high molecular weightpolyethylene oxide, for example below about 62° C., in a plateau-liketemperature profile or (2) the point in time when the temperature of theformulations drops below the curing temperature in a parabolic ortriangular temperature profile. Preferably, the curing step startsaccording to method 3, when the temperature of the formulations reachesa curing temperature of at least about 62° C., at least about 68° C., atleast about 70° C., at least about 72° C. or at least about 75° C.

In still another embodiment (method 4), the curing temperature isdefined to be the target temperature measured using a temperature probe,such as a wire thermocouple, that is placed inside the curing devicenear the formulations, and the starting point of the curing step isdefined to be the point in time when the temperature measured using thetemperature probe reaches the curing temperature. The end point of thecuring step is defined to be (1) the point in time when the heating isstopped or at least reduced and the temperature measured using thetemperature probe subsequently drops below the curing temperature bymore than about 10° C. and/or below the lower limit of the softeningtemperature range of polyethylene oxide, for example below about 62° C.,in a plateau-like temperature profile, or (2) the point in time when thetemperature measured using the temperature probe drops below the curingtemperature in a parabolic or triangular temperature profile.Preferably, the curing step starts when the temperature measured using atemperature probe registers a temperature in the curing device of atleast about 62° C., at least about 68° C., at least about 70° C., atleast about 72° C. or at least about 75° C. In a preferred embodiment,the temperature profile during the curing step shows a plateau-likeform, wherein the curing temperature is at least about 68° C., forexample, about 70° C., and the curing time which is measured accordingto method 4 is preferably in the range of from about 15 minutes to about2 hours or about 60 minutes or about 90 minutes.

If curing takes place in a convection curing device, the curing time canbe measured by any of the methods described above.

In certain embodiments, the curing temperature is defined as a targettemperature range, for example, the curing temperature is defined as atarget inlet air temperature range or a target exhaust air temperaturerange. In such embodiments, the starting point of the curing step isdefined to be the point in time when the lower limit of the targettemperature range is reached, and the end point of the curing step isdefined to be the point in time when the heating is stopped or at leastreduced, and the temperature subsequently drops below the lower limit ofthe target temperature range by more than about 10° C. and/or below thelower limit of the softening temperature range of polyethylene oxide,for example, below about 62° C.

The curing time, i.e., the time period the formulation is subjected tothe curing temperature, which can, for example, be measured according tothe methods described above, is at least about 1 minute or at leastabout 5 minutes. The curing time may vary from about 1 minute to about24 hours, from about 5 minutes to about 20 hours, from about 10 minutesto about 15 hours, from about 15 minutes to about 10 hours, or fromabout 30 minutes to about 5 hours depending on the specific formulationand the curing temperature. According to certain embodiments, the curingtime varies from about 15 minutes to about 30 minutes. According tofurther embodiments, wherein the curing temperature is at least about60° C., at least about 62° C., at least about 68° C., at least about 70°C., at least about 72° C. or at least about 75° C., or varies from about62° C. to about 85° C. or from about 65° C. to about 85° C., then thecuring time is preferably at least about 15 minutes, at least about 30minutes, at least about 60 minutes, at least about 75 minutes, at leastabout 90 minutes or at least about 120 minutes. In preferredembodiments, wherein the curing temperature is, for example, at leastabout 62° C., at least about 68° C., at least about 70° C., at leastabout 72° C. or at least about 75° C., or ranges from about 62° C. toabout 80° C., from about 65° C. to about 80° C., from about 68° C. toabout 80° C., from about 70° C. to about 80° C. or from about 72° C. toabout 80° C., then the curing time is preferably at least about 1minute, at least about 5 minutes, at least about 10 minutes, at leastabout 15 minutes or at least about 30 minutes. In certain suchembodiments, the curing time can be chosen to be as short as possiblewhile still achieving the desired result (e.g., increased tamperresistance). For example, the curing time preferably does not exceedabout 5 hours, does not exceed about 3 hours or does not exceed about 2hours. Preferably, the curing time is in the range of from about 1minute to about 5 hours, from about 5 minutes to about 3 hours, fromabout 15 minutes to about 2 hours, or from about 15 minutes to about 1hour. Any combination of the curing temperatures and the curing times asdisclosed herein lies within the scope of the present invention.

In certain embodiments, the composition is only subjected to the curingtemperature until the polyethylene oxide present in the formulation hasreached its softening temperature and/or at least partially melts. Incertain such embodiments, the curing time may be less than about 5minutes, for example the curing time may vary from greater than 0minutes to about 3 hours, from about 1 minute to about 2 hours or fromabout 2 minutes to about 1 hour. Instant curing is possible by choosinga curing device which allows for an instant heating of the polyethyleneoxide in the formulation to at least its softening temperature, so thatthe high molecular weight polyethylene oxide at least partially melts.Such curing devices are, for example, microwave ovens, ultrasounddevices, light irradiation apparatus such as UV-irradiation apparatus,ultra-high frequency (UHF) fields or any other apparatus known to theperson skilled in the art.

The size of the formulation may determine the required curing time andcuring temperature to achieve the desired tamper resistance.

In certain embodiments, the curing step leads to a decrease in thedensity of the formulation, such that the density of the curedformulation is lower than the density of the formulation prior to thecuring step. Preferably, the density of the cured formulation incomparison to the density of the uncured formulation decreases by atleast about 0.5%. More preferably, the density of the cured formulationin comparison to the density of the uncured formulation decreases by atleast about 0.7%, at least about 0.8%, at least about 1.0%, at leastabout 2.0% or at least about 2.5%.

In certain embodiments, the solid controlled release dosage form iscured at a temperature of at least the softening point of thepolyethylene oxide for at least 1 minute, at least 5 minutes or at least15 minutes.

In other embodiments, the solid controlled release dosage form is curedat a temperature of at least the softening point of the polyethyleneoxide from about 1 minute to about 48 hours, from about 5 minutes toabout 24 hours, from about 15 minutes to about 1 hour or about 30minutes.

The solid controlled release dosage form can be cured, e.g., at atemperature of at least about 60° C., at least about 65° C., at leastabout 70° C., at least about 75° C. or at a temperature of about 72° C.

In alternative embodiments, the solid controlled release dosage form canbe cured at a temperature from about 60° C. to about 90° C., from about62° C. to about 72° C., from about 65° C. to about 85° C., from about70° C. to about 80° C., from about 75° C. to about 80° C. or from about70° C. to about 75° C.

Flattening Procedures

In certain embodiments, dosage forms of the present invention may beflattened without substantially compromising the release of the activeor the integrity of the dosage form. Flatness is described in terms ofthe thickness of the smallest diameter of the flattened shape comparedto the thickness of the smallest diameter of the non-flattened shape.This comparison is expressed in % thickness, based on either (i) thethickness of the smallest diameter of the non-flattened shape when theinitial shape is non-spherical or (ii) the thickness of the diameterwhen the initial shape is spherical. The thickness may be measured usinga thickness gauge (e.g., a digital thickness gauge or digital caliper).The flattening force may be applied by any possible method. For purposesof testing the dosage forms of the present invention, a carver stylebench press may be used (unless otherwise specified) so as to achievethe target flatness or reduced thickness. According to certainembodiments of the invention, the flattening does not result in breakingof the dosage form into separate pieces; however, edge splits and cracksmay occur.

In certain embodiments of the invention, a hammer can be used forflattening a dosage form. In such a process, hammer strikes can bemanually applied from a direction substantially normal to the thickestdimension of the dosage form. The flatness is then described in the samemanner as disclosed above.

In other embodiments, flattening can be measured relative to breakingstrength or hardness tests, as described in Remington's PharmaceuticalSciences, 18th edition, 1990, Chapter 89 “Oral Solid Dosage Forms”,pages 1633-1665, using the Schleuniger Apparatus. In such an embodiment,the dosage form is pressed between a pair of flat plates arranged inparallel such that the force is applied substantially normal to thethickest dimension of the dosage form, thereby flattening the dosageform. The flattening of the dosage form may be described in terms of %flattening, based on the thickness of the dimension being flattenedbefore conducting the breaking strength test. The breaking strength (orhardness) is defined as the force at which the tested dosage formbreaks. Dosage forms that do not break, but which are deformed due to aforce applied are considered to be break-resistant at that particularforce.

A further test to quantify the strength of dosage forms is theindentation test using a Texture Analyzer, such as the TA-XT2 TextureAnalyzer (Texture Technologies Corp., 18 Fairview Road, Scarsdale, N.Y.10583). In this method, a dosage form is placed on top of a stainlesssteel stand with a slightly concave surface and penetrated by thedescending probe of the Texture Analyzer, such as a TA-8A ⅛ inchdiameter stainless steel ball probe. Before starting the measurement,the dosage form is aligned directly under the probe, such that thedescending probe will penetrate the tablet pivotally, i.e., in thecenter of the dosage form, and such that the force of the descendingprobe is applied substantially perpendicular to the diameter andsubstantially in line with the thickness of the dosage form. First, theprobe of the Texture Analyzer starts to move towards the dosage formsample at the pre-test speed. When the probe contacts the dosage formsurface and the trigger force set is reached, the probe continues itsmovement with the test speed and penetrates the dosage form. For eachpenetration depth or distance of the probe, the corresponding force ismeasured. When the probe has reached the desired maximum penetrationdepth, it changes direction and moves back at the post-test speed, whilefurther measurements are taken. The cracking force is defined to be theforce of the first local maximum that is reached in the correspondingforce/distance diagram and is calculated using, for example, the TextureAnalyzer software “Texture Expert Exceed, Version 2.64 English”.

The term “resistant to crushing” is defined for the purposes of certainembodiments of the present invention as referring to dosage forms thatcan at least be flattened with a bench press as described above withoutbreaking to no more than about 60% thickness, preferably no more thanabout 50% thickness, more preferred no more than about 40% thickness,even more preferred no more than about 30% thickness and most preferredno more than about 20% thickness, 10% thickness or 5% thickness.

In certain embodiments, the amount of active agent (e.g., opioidanalgesic) released at 0.5 hour from a flattened dosage form deviates nomore than about 10% points, 15% points or 20% points from the amountreleased at 0.5 hour from a non-flattened dosage form as measured by anin-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C.

In alternative embodiments, the solid controlled release dosage form canbe flattened without breaking, wherein the thickness of the dosage formafter flattening corresponds to no more than about 60% of the thicknessof the dosage form before flattening, no more than about 50% of thethickness of the dosage form before flattening, no more than about 40%of the thickness of the dosage form before flattening, no more thanabout 30% of the thickness of the dosage form before flattening or nomore than about 20% of the thickness of the dosage form beforeflattening.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

EXAMPLES

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction of the invention.

Example 1

A 400 mg tablet (Tablet A) including 20 mg of hydrocodone bitartrate wasprepared using high molecular weight polyethylene oxide (PEO 303-MW7,000,000), as set forth in Table 1 below.

TABLE 1 (Tablet A) Hydrocodone Total % of Tooling Size (mg) wtHydrocodone (mm) Core 16 200 8 7.94 Shell 4 200 2 10.32 Total 20 400 10

To prepare the core, a single station Manesty Type F 3 tablet press wasequipped with 7.94 mm, round, standard concave plain tooling. A powderedaliquot of the core blend, as set forth above in Table 1, was weighedout to target weight of 200 mg, charged into the die, and compressed toform the core of Tablet A.

To prepare the shell, the single station Manesty Type F 3 tablet presswas equipped with 10.32 mm, round, standard concave plain tooling. 100mg of the shell blend, as set forth in Table 1, was placed in the die.The tablet core as prepared above was manually centered in the die (ontop of the powder bed), and an additional 100 mg of the shell blend wasplaced on top of the tablet in the die. The materials were then manuallycompressed by turning the compression wheel to form compression coatedTablet A.

Several compression coated Tablet A tablets prepared as above wereplaced onto a tray, which was placed in a Hotpack model 435304 oventargeting 72° C. for 30 minutes to cure.

Dissolution of cured Tablet A tablets was then tested in a USP Apparatus1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. Results are shown against the results of theformulations of Examples 2-4 in FIG. 1.

Example 2

A 500 mg tablet (Tablet B) including 20 mg of hydrocodone bitartrate wasprepared using high molecular weight polyethylene oxide (PEO 303-MW7,000,000), as set forth in Table 2 below.

TABLE 2 (Tablet B) Hydrocodone Total % of Tooling Size (mg) wtHydrocodone (mm) Core 16 300 5.3 8.73 Shell 4 200 2 11.11 Total 20 500 4

To prepare the core, a single station Manesty Type F 3 tablet press wasequipped with 8.73 mm, round, standard concave plain tooling. A powderedaliquot of the core blend, as set forth above in Table 2, was weighedout to target weight of 300 mg, charged into the die and compressed toform the core of Tablet B.

To prepare the shell, the single station Manesty Type F 3 tablet presswas equipped with 11.11 mm, round, standard concave plain tooling. Thefirst portion of the 200 mg shell blend, as set forth in Table 2, wasplaced in the die. The tablet core as prepared above was manuallycentered in the die (on top of the powder bed), and the remainingportion of the 200 mg shell blend was placed on top of the tablet in thedie. The materials were then manually compressed by turning thecompression wheel to form compression coated Tablet B.

Several compression coated Tablet B tablets prepared as above wereplaced onto a tray, which was placed in a Hotpack model 435304 oventargeting 72° C. for 30 minutes to cure.

Dissolution of cured Tablet B tablets was then tested in a USP Apparatus1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. Results are shown against the results of theformulations of Examples 1 and 3-4 in FIG. 1.

Example 3

A 500 mg tablet (Tablet C) including 20 mg of hydrocodone bitartrate wasprepared using high molecular weight polyethylene oxide (PEO 303-MW7,000,000), as set forth in Table 3 below.

TABLE 3 (Tablet C) Hydrocodone Total % of Tooling Size (mg) wtHydrocodone (mm) Core 16 300 5.3 9.53 Shell 4 200 2 11.11 Total 20 500 4

To prepare the core, a single station Manesty Type F 3 tablet press wasequipped with 9.53 mm, round, standard concave plain tooling. A powderedaliquot of the core blend, as set forth above in Table 3, was weighedout to target weight of 300 mg, charged into the die and compressed toform the core of Tablet C.

To prepare the shell, the single station Manesty Type F 3 tablet presswas equipped with 11.11 mm, round, standard concave plain tooling. Afirst portion of the 200 mg shell blend, as set forth in Table 3, wasplaced in the die. The tablet core as prepared above was manuallycentered in the die (on top of the powder bed), and the remainingportion of the 200 mg shell blend was placed on top of the tablet in thedie. The materials were then manually compressed by turning thecompression wheel to form compression coated Tablet C.

Several compression coated Tablet C tablets prepared as above wereplaced onto a tray, which was placed in a Hotpack model 435304 oventargeting 72° C. for 30 minutes to cure.

Dissolution of cured Tablet C tablets was then tested in a USP Apparatus1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. Results are shown against the results of theformulations of Examples 1-2 and 4 in FIG. 1.

Example 4

A 475 mg tablet (Tablet D) including 20 mg of hydrocodone bitartrate wasprepared using high molecular weight polyethylene oxide (PEO 303-MW7,000,000), as set forth in Table 4 below.

TABLE 4 (Tablet D) Hydrocodone Total % of Tooling Size (mg) wtHydrocodone (mm) Core 14 175 8 7.94 Shell 6 300 2 11.11 Total 20 475 4.2

To prepare the core, a single station Manesty Type F 3 tablet press wasequipped with 7.94 mm, round, standard concave plain tooling. A powderedaliquot of the core blend, as set forth in Table 4, was weighed out totarget weight of 175 mg, charged into the die and compressed to form thecore of Tablet D.

To prepare the shell, the single station Manesty Type F 3 tablet presswas equipped with 11.11 mm, round, standard concave plain tooling. Afirst portion of the 300 mg shell blend, as set forth in Table 4, wasplaced in the die. The tablet core as prepared above was manuallycentered in the die (on top of the powder bed), and the remainingportion of the 300 mg shell blend was placed on top of the tablet in thedie. The materials were then manually compressed by turning thecompression wheel to form compression coated Tablet D.

Several compression coated Tablet D tablets prepared as above were thenplaced onto a tray, which was placed in a Hotpack model 435304 oventargeting 72° C. for 30 minutes to cure.

Dissolution of cured Tablet D tablets was then tested in a USP Apparatus1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. Results are shown against the results of theformulations of Examples 1-3 in FIG. 1.

Example 5

A 500 mg tablet (Tablet E) including 120 mg of hydrocodone was preparedusing low molecular weight polyethylene oxide (PEO 205-MW 600,000) forthe core and using high molecular weight polyethylene oxide (PEO 303-MW7,000,000) for the shell, as set forth in Table 5 below.

TABLE 5 (Tablet E) Hydrocodone Total % of Tooling Size (mg) wtHydrocodone (mm) Core 96 300 32 8.73 Shell 24 200 12 11.11 Total 120 50024

To prepare the core, a single station Manesty Type F 3 tablet press wasequipped with 8.73 mm, round, standard concave plain tooling. A powderedaliquot of the core blend, as set forth in Table 5, was weighed out totarget weight of 300 mg, charged into the die and compressed to form thecore of Tablet E.

To prepare the shell, the single station Manesty Type F 3 tablet presswas equipped with 11.11 mm, round, standard concave plain tooling. Afirst portion of the 200 mg shell blend, as set forth in Table 5, wasplaced in the die. The tablet core as prepared above was manuallycentered in the die (on top of the powder bed), and the remainingportion of the 200 mg shell blend was placed on top of the tablet in thedie. The materials were manually compressed by turning the compressionwheel to form compression coated Tablet E.

Several compression coated Tablet E tablets prepared as above were thenplaced onto a tray, which was placed in a Hotpack model 435304 oventargeting 72° C. for 30 minutes to cure.

Dissolution of cured Tablet E tablets was then tested in a USP Apparatus1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. Results are shown against the results of theformulations of Examples 5 and 6 in FIG. 2.

Example 6

A 500 mg tablet (Tablet F) including 120 mg of hydrocodone was preparedusing high molecular weight polyethylene oxide (PEO 303-MW 7,000,000),as set forth in Table 6 below.

TABLE 6 (Tablet F) Hydrocodone Total % of Tooling Size (mg) wtHydrocodone (mm) Core 96 300 32 8.73 Shell 24 200 12 11.11 Total 120 50024

To prepare the core, a single station Manesty Type F 3 tablet press wasequipped with 8.73 mm, round, standard concave plain tooling. A powderedaliquot of the core blend, as set forth in Table 6, was weighed out totarget weight of 300 mg, charged into the die and compressed to form thecore of Tablet F.

To prepare the shell, the single station Manesty Type F 3 tablet presswas equipped with 11.11 mm, round, standard concave plain tooling. Afirst portion of the 200 mg shell blend, as set forth in Table 6, wasplaced in the die. The tablet core as prepared above was manuallycentered in the die (on top of the powder bed), and the remainingportion of the 200 mg shell blend was placed on top of the tablet in thedie. The materials were manually compressed by turning the compressionwheel to form compression coated Tablet F.

Several compression coated Tablet F tablets prepared as above were thenplaced onto a tray, which was placed in a Hotpack model 435304 oventargeting 72° C. for 30 minutes to cure.

Dissolution of Tablet F tablets was then tested in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. Results are shown against the results of theformulations of Examples 5 and 6 in FIG. 2.

Examples 7-12

Six different compression coated tablets (designated as Tablets G-L)containing a total of either 20 mg of hydrocodone bitartrate (Tablets G,H and I) or 120 mg of hydrocodone bitartrate (Tablets J, K and L) wereprepared according to Table 7 (20 mg) or Table 8 (120 mg) below.

TABLE 7 (Tablets G, H, I) 20 mg Formulation Formulation Formulation G HI Component mg/tablet mg/tablet mg/tablet Core Hydrocodone Bitartate 1616 16 Microcrystalline 1.09 1.09 1.09 Cellulose, Avicel PH 101Hydroxypropyl 1.09 1.09 1.09 Cellulose, Klucel EXF PEO (Mw = 600,000)280.32 280.32 280.32 POLYOX WSR 205 Magnesium Stearate 1.5 1.5 1.5Subtotal 300 300 300 Dry Coat Hydrocodone Bitartate 4 4 4Microcrystalline 0.27 0.27 0.27 Cellulose, Avicel PH 101 Hydroxypropyl0.27 0.27 0.27 Cellulose, Klucel EXF PEO (Mw = 7,000,000) 393.26 293.81194.36 POLYOX WSR 303 FP Magnesium Stearate 2 1.5 1 D&C Yellow No. 100.2 0.15 0.1 Aluminum Lake Subtotal 400 300 200 Cosmetic Coat OpadryWhite 28 24 20 Y-5-18024-A Total 728 624 520

TABLE 8 (Tablets J, K, L) 120 mg Formulation Formulation Formulation J KL Component mg/tablet mg/tablet mg/tablet Core Hydrocodone Bitartate 9696 96 Microcrystalline 6.54 6.54 6.54 Cellulose, Avicel PH 101Hydroxypropyl 6.54 6.54 6.54 Cellulose, Klucel EXF PEO (Mw = 600,000)189.42 189.42 189.42 POLYOX WSR 205 Magnesium Stearate 1.5 1.5 1.5Subtotal 300 300 300 Dry Coat Hydrocodone Bitartate 24 24 24Microcrystalline 1.64 1.64 1.64 Cellulose, Avicel PH 101 Hydroxypropyl1.64 1.64 1.64 Cellulose, Klucel EXF PEO (Mw = 7,000,000) 370.52 271.07171.62 POLYOX WSR 303 FP Magnesium Stearate 2 1.5 1 D&C Red No. 30 0.20.15 0.1 Aluminum Lake Subtotal 400 300 200 Cosmetic Coat Opadry Pink 2824 20 Y-S-1-14518A Total 728 624 520

A high-shear granulator (Collette 75 L) was charged with the hydrocodonebitartrate, the microcrystalline cellulose and thehydroxypropylcellulose. Water was added to the mixture (e.g., 8-15%)with the propeller and chopper on. The wet granulation was passedthrough the coarse screen of a Quadro Comil milling device. The screenedwet granulation was dried in a Vector VFC-3 fluid bed dryer. The driedgranulation was passed through the fine screen of the Quadro Comilmilling device.

A 16 Q “V” blender was charged with the PEO POLYOX WSR 205 and themilled granulation, and blended for 5 minutes. Screened magnesiumstearate was added to the mixture and blended for 1 minute to preparethe core blend.

A 16 Q “V” blender was charged with the PEO POLYOX WSR 303, the D&C RedNo. 30 aluminum lake, and the milled granulation, and blended for 5minutes. Screened magnesium stearate was added to the mixture andblended for 1 minute to prepare the dry coat blend.

The core blend and dry coat blend were compressed into dry coatedtablets on a DryCota Press. The core blend was loaded into the side onehopper and the core weight was adjusted to target 300 mg. Then the drycoat blend was loaded into the side two hopper and the total tabletweight was adjusted to target. After weight adjustment, the compressionrun was started and the press was run at, e.g., 6 rpm.

Approximately 10 kg of the compression coated tablets were weighed outand spray-coated with the Opadry coating suspension to a target weightgain of about 1.0% (by wt.) in a perforated 24 inch Compu-Lab pancoater. The spray-coating was carried out as follows. The tablet bed waswarmed by setting the inlet air temperature to 55° C. Once the exhausttemperature reached 39° C., the film coating began at a pan speed of 12rpm and a spray rate of approximately 44 mL/min. Film coating wascontinued until the target 1% weight gain was achieved (this was apartial coating prior to the curing in step x, as the final coating of4% weight gain in step xii would become sticky during curing).

The partially coated tablets were cured in the perforated pan coater.The inlet temperature was set to 85° C. at a pan speed of approximately10 rpm. The tablets were cured at an exhaust temperature of 72° C. forapproximately 30 minutes.

After curing, the tablets were cooled in the rotating pan by setting theinlet temperature to 22° C. Cooling was continued until the exhausttemperature was less than 28° C.

The cured tablets were then spray-coated with additional coatingsuspension to attain a target final weight gain of 4.0% (by wt.,inclusive of the previous 1% coating) in the perforated pan coater at apan speed of 12 rpm and spray rate of approximately 44 mL/min.

The film coated tablets were transferred into a tared polyethylene lineddrum.

The dissolution results (% active released over time) for thesecompression coated 20 mg and 120 mg tablets are presented in FIG. 3 andTables 9 and 10 below.

TABLE 9 20 mg 20 mg 20 mg Slow (G) Med. (H) Fast (I) Disso % active %active % active Time (h) released released released 1 5 6 8 2 8 10 14 414 19 28 8 33 43 55 12 56 66 81 18 81 91 106 24 99 102 107

TABLE 10 120 mg 120 mg 120 mg Slow (J) Med. (K) Fast (L) Disso % active% active % active Time (h) released released released 1 5 6 8 2 8 10 154 14 20 29 8 35 47 57 12 59 72 82 18 86 100 98 24 102 103 100

As indicated by the dissolution of the above examples, factors whichinfluence the dissolution of active agent from the dosage forms are thecore:shell weight ratio and the tablet weight. Further, dissolution datapresented above demonstrates that formulations of the present inventionexhibit substantially zero order release as disclosed herein.

Example 13

A randomized, open-label, crossover study in healthy adult male andfemale subjects was conducted with the hydrocodone formulations (HYD) ofExamples 7-12. The study was comprised of Iterations (a process ofrepeating the study design each time with a unique group of subjectsundergoing a set of predefined treatments). The following Iterationswere conducted:

Iteration 1: N=36

Randomized, single-dose, 3 treatment, 3 period crossover.

HYD 20 mg, slow release tablet, fasted state (Tablet G)

HYD 20 mg, medium release tablet, fasted state (Tablet H)

HYD 20 mg, fast release tablet, fasted state (Tablet I)

Iteration 2: N=36

Randomized, single-dose, 3 treatment, 3 period crossover.

HYD 120 mg, slow release tablet, fasted state (Tablet J)

HYD 120 mg, medium release tablet, fasted state (Tablet K)

HYD 120 mg, fast release tablet, fasted state (Tablet L)

Iteration 3: N=16

Randomized, single-dose, 2 treatment, 2 period crossover.

HYD 120 mg, slow release tablet, fasted state (Tablet J)

HYD 120 mg, slow release tablet, fed state (Tablet J)

The formulations were each administered orally with 8 oz. (240 mL) wateras a single dose in the fasted or fed state as indicated.

As this study was conducted in healthy human subjects, the opioidantagonist naltrexone hydrochloride was administered to minimizeopioid-related adverse events.

Subject Selection Screening Procedures

The following screening procedures were performed for all potentialsubjects at a screening visit conducted within 28 days prior to firstdose administration:

-   -   Informed consent.    -   Informed consent for optional pharmacogenomic sampling.    -   Informed consent for optional hair sampling.    -   Weight, height, body mass index (BMI), and demographic data.    -   Evaluation of inclusion/exclusion criteria.    -   Medical and medication history, including concomitant        medication.    -   Vital signs (systolic/diastolic blood pressure, pulse rate,        respiration rate, oral temperature) after being seated for        approximately 5 minutes and SpO₂    -   Additional vital signs (systolic/diastolic blood pressure, and        pulse rate) after standing for approximately 2 minutes.    -   HDYF? Inquiry was performed at the same time vital signs were        measured.    -   Routine physical examination.    -   Clinical laboratory evaluations following at least a 4 hour fast        (including biochemistry, hematology, and urinalysis).    -   12-lead ECG. QTcF not to exceed 450 msec.    -   Screens for hepatitis (including hepatitis B surface antigen        [HBsAg], hepatitis C antibody [anti-HCV]).    -   Screens for alcohol, cotinine, and selected drugs of abuse.    -   Serum pregnancy test, female subjects only; Serum follicle        stimulating hormone (FSH) postmenopausal females only.    -   Serum pregnancy test (female subjects only).    -   Serum follicle stimulating hormone (FSH) test (postmenopausal        females only).

Inclusion Criteria

-   -   Subjects who met the following criteria were included in the        study.    -   Provided written informed consent.    -   Males and females aged 18 to 50, inclusive.    -   Body weight ranging from 50 to 100 kg (110 to 220 lbs) and a BMI        18 to 34 (kg/m²), inclusive.    -   Healthy and free of significant abnormal findings as determined        by medical history, physical examination, vital signs, and ECG.    -   Females of child-bearing potential must be using an adequate and        reliable method of contraception (i.e, barrier with additional        spermicidal foam or jelly, intra-uterine device, hormonal        contraception). Females who are post-menopausal must have been        postmenopausal ≧1 year and have elevated serum FSH.    -   Willing to eat the food supplied during the study.    -   Will refrain from strenuous exercise during the entire study.        Subjects will not begin a new exercise program nor participate        in any unusually strenuous physical exertion.

Exclusion Criteria

The following criteria excluded potential subjects from the study.

-   -   Females who are pregnant (positive beta human chorionic        gonadotropin test) or lactating.    -   Current or recent (within 5 years) history of drug or alcohol        abuse.    -   History or any current conditions that might interfere with drug        absorption, distribution, metabolism or excretion.    -   Use of an opioid-containing medication in the past 30 days        preceding the initial dose in this study.    -   History of known sensitivity to hydrocodone, naltrexone or        related compounds.    -   Any history of frequent nausea or emesis regardless of etiology.    -   Any history of seizures or head trauma with sequelae.    -   Participation in a clinical drug study during the 30 days        preceding the initial dose in this study.    -   Any significant illness during the 30 days preceding the initial        dose in this study.    -   Use of any medication including thyroid hormonal therapy        (hormonal contraception is allowed), vitamins, herbal and/or        mineral supplements during the 7 days preceding the initial        dose.    -   Abnormal cardiac conditions including any of the following:        -   QTc interval ≧450 msec (calculated using Fridericia's            correction) at screening.        -   QTc interval ≧480 msec (calculated using Fridericia's            correction) during Treatment period.    -   Refusal to abstain from food 10 hours preceding and 4 hours        following study drug administration and to abstain from caffeine        or xanthine containing beverages entirely during each        confinement.    -   Refusal to abstain from consumption of alcoholic beverages 48        hours prior to initial study drug administration (day 1) and        anytime during study.    -   History of smoking or use of nicotine products within 45 days of        study drug administration or a positive urine cotinine test.    -   Blood or blood products donated within 60 days prior to study        drug administration or anytime during the study and for 30 days        after completion of the study, except as required by this        protocol.    -   Plasma donated within 14 days prior to study drug administration        or any time during the study, except as required by this        protocol.    -   Positive results of urine drug screen or alcohol screen.    -   Positive results of HBsAg, anti-HCV.    -   Positive naloxone HCl challenge test.    -   Presence of Gilbert's Syndrome, or any known hepatobiliary        abnormalities.    -   For the optional hair sampling portion of the study only, an        insufficient amount of scalp hair to provide an adequate sample.    -   The investigator believes the subject to be unsuitable for        reason(s) not specifically stated in the exclusion criteria.

Subjects meeting all the inclusion criteria and none of the exclusioncriteria were randomized into the study.

Each subject was assigned a unique subject number at screening.Assignment of subject numbers was in ascending order and no numbers wereomitted. Subject numbers were used on all study documentation.

Check-in Procedures

On Day −1 of Period 1 only, subjects were admitted to the study unit andreceived a Naloxone HCl challenge test. The results of the test had tobe negative for subjects to continue in the study. Vital signs and SPO₂were measured prior to and following the Naloxone HCl.

The following procedures were also performed for all subjects atCheck-in for each period:

-   -   Verification of inclusion/exclusion criteria, including        verification of willingness to comply with caffeine and xanthine        restriction criteria.    -   Vital signs (after being seated for approximately 5 minutes) and        SpO2.    -   HDYF (How do you feel) ? Inquiry was performed at the same time        vital signs were measured.    -   Clinical laboratory evaluations (day −1, period 1 only)        including biochemistry (fasting for at least 4 hours),        hematology and urinalysis) were collected after vital signs and        SpO₂ were measured.    -   Screen for alcohol (via urine or blood alcohol or breathalyzer        test), cotinine, and selected drugs of abuse (via urine        testing).    -   Urine pregnancy test (for all female subjects).    -   Concomitant medication monitoring and recording.    -   AE monitoring and recording.

For subjects to continue their participation in the study, the resultsof the drug screen (including alcohol and cotinine) had to be availableand negative prior to dosing. In addition, continued compliance withconcomitant medication and other restrictions were verified at Check-inand throughout the study in the appropriate source documentation.

Treatment Period Procedures

Treatments to be studied were predetermined for each Iteration. Withinan Iteration, as data became available, treatments were dropped betweencohorts. Dropped treatments were replaced with repeats of remainingtreatments.

-   -   Prior to the first dose in period 1, subjects were randomized to        a treatment sequence.    -   Subjects received naltrexone HCl tablets (50 mg) with 240 mL of        water at −12 h prior to study drug dosing.    -   Prior to study drug administration (except period 1), subjects        had chemistry (fasting for at least 4 hours), hematology and        urinalysis tests performed.    -   Subjects were administered the study drug with 240 mL of water        as follows:        -   For Fasted Treatment:        -   Following a 10-hour overnight fast, subjects were            administered study drug with 240 mL of water. Subjects            receiving fasted treatment continued fasting from food for 4            hours following dosing.        -   For Fed Treatments:        -   Following a 10-hour overnight fast, the subjects were fed a            standard meal (FDA high-fat breakfast) 30 minutes prior to            administration of study drug with 240 mL of water. No food            was allowed for at least 4 hours post-dose. It was made very            clear to the subjects that all of the meal should be            consumed within the designated time-frame.        -   Subjects were standing or in an upright sitting position            while receiving their dose of study drug.        -   Fasting was not required for nondosing study days.    -   Subjects received naltrexone HCl 50-mg tablets with 240 mL of        water at −12, 0, 12, 24, and 36 hours relative to each study        drug dosing.    -   For subjects receiving hydrocodone doses of 60 mg or more, SpO₂        was monitored continuously beginning prior to dosing and        continuing through 24 hours post-dose.    -   Vital signs (after being seated for approximately 5 minutes) and        SpO₂, were obtained pre-dose and at hour 1, 2, 4, 6, 8, 12, 24,        36, 48, and 72 hour post dose for each period.    -   HDYF (How do you feel) ? Inquiry was performed at the same time        vital signs were measured.    -   Subjects had biochemistry (fasting for at least 4 hours),        hematology, and urinalysis tests performed 24 hours post-dose.    -   In addition, 12-lead ECGs were performed for each subject        pre-dose and approximately 12, 24 and 48 hours post-dose. If        QTcF exceeded 480 msec the subject was discontinued due to the        reason of Adverse Event.    -   Blood samples for determining hydrocodone plasma concentrations        were obtained for each subject at pre-dose and at 0.5, 1, 1.5,        2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 14, 18 24, 36, 48, and 72        hours post-dose for each period.    -   Subjects were confined to the unit from check-in to the unit on        the day before dosing until the time that their 48 h procedures        were completed. The subjects returned to the unit for the 72 h        procedures.    -   During the study, AEs and concomitant medications were recorded.

In addition, the subjects were informed that it is very important toreport any/all episodes of emesis to the study staff immediately andthat this information is crucial to the proper conduct and outcome ofthe trial. The subjects were informed that they would not be penalizedin any way due to reporting cases of emesis. The study staff wasinstructed to carefully document any/all cases of emesis.

Study Completion Procedures

The following procedures were performed at the study site for allsubjects at end-of-study (study completion), 7 to 10 days afterreceiving their last dose of study drug or upon early discontinuationfrom the study.

-   -   Concomitant medication evaluation.    -   Vital signs (after being seated for approximately 5 minutes) and        SpO₂.    -   HDYF? Inquiry was performed at the same time vital signs are        measured.    -   Physical examination.    -   12-Lead ECG.    -   Clinical laboratory evaluations (including biochemistry [fasted        at least 4 hours], hematology, and urinalysis).    -   AE evaluations.    -   Serum pregnancy test (for female subjects only).

The draft results are set forth in FIGS. 4-6 and Table 13 below:

TABLE 13 Summary of Draft Plasma Hydrocodone Pharmacokinetic ParametersIteration 1: Iteration 2: Iteration 3: HYD HYD 20 mg HYD 120 mg 120 mgSlow Medium Fast Slow Medium Fast Slow (G) (H) (I) (J) (K) (L) (J) Slow(J) Parameter Fasted Fasted Fasted Fasted Fasted Fasted Fasted Fed(Unit) Statistic (N = 36) (N = 36) (N = 36) (N = 36) (N = 36) (N = 36)(N = 14) (N = 16) AUCt MEAN 302 323 330 2028 2074 2048 1921 2025 (ng *h/mL) SD 138 101 90 439 440 514 369 420 MIN 43 95 78 1315 1043 430 14171135 MAX 619 557 499 2911 2869 2917 2586 2716 AUCinf Mean 312 326 3292037 2083 2055 1933 2032 (ng * h/mL) SD 142 102 90 442 443 516 374 420Min 44 97 83 1320 1046 430 1427 1136 Max 623 564 507 2935 2908 2924 25942717 Cmax Mean 15.0 17.4 20.9 119 138 142 110 166 (ng/mL) SD 6.4 5.8 7.235.8 35.3 39.3 30 34.2 Min 4.3 7.5 7.7 55.2 76.7 35.6 67 96.2 Max 30.731.3 39.0 227 241 239 162 240 Tmax (h) Mean 15.2 13.7 11.4 15.4 12.710.7 15 12.0 SD 4.7 2.6 3.5 2.9 1.7 2.0 3 1.0 Min 5 8 6 10 10 6 12 10Median 14 14 12 14 12 10 14 12 Max 24 18 24 24 18 14 24 14 T½ (h) Mean8.3 7.6 9.0 7.1 7.6 7.1 7.7 7.8 SD 3.1 2.9 4.9 2.4 3.3 2.5 2.4 4.6 Min4.1 4.5 4.4 4.5 4.2 4.1 4.0 3.8 Max 15.3 17.3 25.2 16.0 17.9 13.4 12.421.4 Tlag (h) Mean 0.15 0.11 0.13 0.06 0.03 0.01 0.03 0.06 SD 0.23 0.210.22 0.16 0.12 0.09 0.13 0.17 Min 0 0 0 0 0 0 0 0 Max 0.5 0.5 0.5 0.50.5 0.5 0.5 0.5 C24/Cmax Mean 0.57 0.45 0.30 0.52 0.32 0.23 N/A N/A SD0.28 0.20 0.18 0.21 0.15 0.10 N/A N/A Min 0.03 0.10 0.06 0.17 0.11 0.07N/A N/A Max 1.00 0.84 1.00 1.00 0.74 0.48 N/A N/A

Examples 14-20

Seven different compression coated tablets (designated as Tablets M-S)containing a total of 20, 30, 40, 60, 80, 100 or 120 mg of hydrocodonebitartrate, respectively, were prepared according to Tables 14 (TabletsM, N, O, P) and 15 (Tablets Q, R, S) below.

TABLE 14 (Tablets M, N, O, P) Formula- Formula- Formula- Formula- tion Mtion N tion O tion P (20 mg) (30 mg) (40 mg) (60 mg) Component mg/tabletmg/tablet mg/tablet mg/tablet Core Hydrocodone Bitartate 16.000 24.00032.000 48.000 Microcrystalline 1.091 1.636 2.182 3.273 Cellulose, AvicelPH 101 Hydroxypropyl 1.091 1.636 2.182 3.273 Cellulose, Klucel EXFPurified Water 279.918 270.827 261.736 243.555 PEO (Mw = 600,000) POLYOXWSR 205 FP Magnesium Stearate 1.500 1.500 1.500 1.500 FD&C Yellow No. 60.400 0.400 0.400 0.400 Aluminum Lake Subtotal 300 300 300 300 Dry CoatHydrocodone Bitartate 4.000 6.000 8.000 12.000 Microcrystalline 0.2730.409 0.545 0.818 Cellulose, Avicel PH 101 Hydroxypropyl 0.273 0.4090.545 0.818 Cellulose, Klucel EXF Purified Water 393.455 391.182 388.909384.364 PEO (Mw = 7,000,000) POLYOX WSR 303 FP Magnesium Stearate 2.0002.000 2.000 2.000 Subtotal 400 400 400 400 Cosmetic Coat Opadry Clear 1414 14 14 85F19250 Opadry Green 21 85F110049 Opadry Yellow 21 85F120034Opadry Gray 21 85F175009 Opadry Beige 21 85F170015 Opadry Pink 85F140044Opadry Blue 85F105039 Opadry White 85F18422 Total 735 735 735 735

TABLE 15 (Tablets Q, R, S) Formulation Formulation Formulation Q R S (80mg) (100 mg) (120 mg) Component mg/tablet mg/tablet mg/tablet CoreHydrocodone Bitartate 64.000 80.000 96.000 Microcrystalline 4.364 5.4556.545 Cellulose, Avicel PH 101 Hydroxypropyl Cellulose, 4.364 5.4556.545 Klucel EXF Purified Water 225.373 207.191 189.009 PEO (Mw =600,000) POLYOX WSR 205 FP Magnesium Stearate 1.500 1.500 1.500 FD&CYellow No. 6 0.400 0.400 0.400 Aluminum Lake Subtotal 300 300 300 DryCoat Hydrocodone Bitartate 16.000 20.000 24.000 Microcrystalline 1.0911.364 1.636 Cellulose, Avicel PH 101 Hydroxypropyl Cellulose, 1.0911.364 1.636 Klucel EXF Purified Water 379.818 375.273 370.727 PEO (Mw =7,000,000) POLYOX WSR 303 FP Magnesium Stearate 2.000 2.000 2.000Subtotal 400 400 400 Cosmetic Coat Opadry Clear 14 14 14 85F19250 OpadryGreen 85F110049 Opadry Yellow 85F120034 Opadry Gray 85F175009 OpadryBeige 85F170015 Opadry Pink 21 85F140044 Opadry Blue 21 85F105039 OpadryWhite 21 85F18422 Total 735 735 735

A high shear mixer was charged with the hydrocodone bitartrate, themicrocrystalline cellulose, and the hydroxypropyl cellulose.

The dry mix mixture was mixed for one (1) minute at low speed and thechopper off, then mixed at high speed with the chopper on. Water wasadded to the mixture until the desired amount of water had been added,producing a wet granulation.

The wet granulation was then passed through a screening mill to de-lump,and transferred to a fluid bed dryer to dry.

The dry mixture was then passed through a fine mesh screen until thetarget particle size range was achieved (<1.0%).

The dried screened granulation was then passed through a screening milland the active granulation was collected in stainless steel containers.A V-blender was charged with approximately half of the polyethyleneoxide (POLYOX WSR-205); the appropriate amount of active granulation(adjusted for assay); the aluminum lake; and the remaining polyethyleneoxide (POLYOX WSR-205), and the mixture was blended for 10 minutes.

The V-blender was then charged with the magnesium stearate and themixture was blended for 2 minutes and discharged into stainless steeldrums.

A V-blender was charged with approximately half of the polyethyleneoxide (POLYOX WSR-303); the appropriate amount of active granulation(adjusted for assay); and the remaining polyethylene oxide (POLYOXWSR-303), and the mixture was blended for 10 minutes.

The V-blender was then charged with the magnesium stearate; blended for2 minutes and discharged into stainless steel drums.

The left side of the press was set up with 8.75 mm, round, shallowconcave tooling, and the right side of the press with 12 mm, round,shallow concave, bevel edge tooling.

The core blend (colored) was then charged into the left side hopper(gravity feed system) to initiate core compression.

The core weight was adjusted to the target weight (300 mg, +/−5%).

The dry coat blend (white to off white) was then charged into the rightside hopper (gravity feed system) to initiate tablet compression.

The initial dry coat fill and subsequent dry coat fill were adjustedafter core placement to the target total tablet weight of 700 mg (300 mgcore+400 mg dry coat).

For the Opadry color dispersion (target 20% solids), a mixing vessel wascharged with the appropriate amount of purified water the mixer speedwas adjusted to form a vortex. Opadry color powder was added to thevessel over a period of 2-5 minutes, and mixed until a homogenousdispersion is produced (minimum 1 hour).

For the Opadry clear dispersion (target 7.5% solids) a separate mixingvessel was charged with the appropriate amount of purified water and themixer speed was adjusted to form a vortex. Opadry clear powder was addedto the vessel over a period of 2-5 minutes (target 3 min), and mixeduntil a homogenous dispersion is produced (minimum 1 hour).

The compression coated tablets were then transferred to a perforatedcoating pan and film-coated with the Opadry color dispersion to a targetweight gain of 0.7%-1.5%.

The heating temperature was increased and the tablets were cured to atarget exhaust temperature of 72° C. for approximately 30 minutes, thencooled.

The tablet coating was continued with the Opadry color dispersion to atarget weight gain of 3% including the weight gain from the previouscoating.

The tablets were then film-coated with the Opadry clear dispersion to afinal target weight gain of 5%.

The dissolution results (% active released over time) for thesecompression coated 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mgtablets are presented in Table 16 below.

TABLE 16 The Dissolution Results of Compression Coated 20, 40, 60, 80,120 mg Tablets (SGF, n = 12) Diss 20 mg % 40 mg % 60 mg % 80 mg % 120 mg% Time active active active active active (h) released released releasedreleased released 1 4 4 4 5 4 2 7 7 7 7 7 4 13 13 13 13 14 6 21 21 21 2122 8 31 32 32 31 32 10 42 43 44 43 45 12 53 55 55 55 57 14 62 65 66 6568 16 71 74 75 74 77 18 79 82 83 83 86 20 87 91 92 91 93 22 95 99 98 9899 24 99 102 102 101 101

Example 21

A randomized, open-label, single-dose, 5-treatment, 4-period crossover,incomplete block study in healthy adult male and female subjects wasconducted with the hydrocodone formulations (HYD) of Examples 14-20. Thestudy was comprised of a maximum of 5 treatments, across 4 periods.

The HYD tablet strength, or doses studied were:

-   -   1×20 mg HYD tablet    -   1×40 mg HYD tablet    -   1×60 mg HYD tablet    -   1×80 mg HYD tablet    -   1×120 mg HYD tablet

The treatments were each administered orally with 8 oz. (240 mL) wateras a single dose in the fasted state.

As this study was conducted in healthy human subjects, the opioidantagonist naltrexone hydrochloride was administered to minimizeopioid-related adverse events.

Subject Selection Screening Procedures

The following screening procedures were performed for all potentialsubjects at a screening visit conducted within 28 days prior to firstdose administration:

-   -   Informed consent.    -   Informed consent for optional pharmacogenomic sampling.    -   Informed consent for optional hair sampling.    -   Weight, height, body mass index (BMI), and demographic data.    -   Evaluation of inclusion/exclusion criteria.    -   Medical and medication history, including concomitant        medication.    -   Vital signs (systolic/diastolic blood pressure, pulse rate,        respiration rate, oral temperature) after being seated for        approximately 5 minutes and SpO₂    -   Additional vital signs (systolic/diastolic blood pressure, and        pulse rate) after standing for approximately 2 minutes.    -   HDYF? Inquiry was performed at the same time vital signs were        measured.    -   Routine physical examination.    -   Clinical laboratory evaluations following at least a 4 hour fast        (including biochemistry, hematology, and urinalysis).    -   12-lead ECG. QTcF not to exceed 450 msec.    -   Screens for hepatitis (including hepatitis B surface antigen        [HBsAg], hepatitis C antibody [anti-HCV]).    -   Screens for alcohol, cotinine, and selected drugs of abuse.    -   Serum pregnancy test, female subjects only; Serum follicle        stimulating hormone (FSH) postmenopausal females only.    -   Serum pregnancy test (female subjects only).    -   Serum follicle stimulating hormone (FSH) test (postmenopausal        females only).

Inclusion Criteria

Subjects who met the following criteria were included in the study.

-   -   Provide written informed consent.    -   Males and Females aged 18 to 50, inclusive.    -   Willing to eat the food supplied during the study.    -   Body weight ranging from 50 to 100 kg (110 to 220 lbs) and a BMI        of 18 to 30 (kg/m2), inclusive.    -   Willing to refrain from strenuous exercise through the end of        study visit. Subjects will not begin a new exercise program nor        participate in any unusually strenuous physical exertion.    -   Healthy and free of significant abnormal findings as determined        by medical history, physical examination, clinical laboratory        values, vital signs, and ECG.    -   Females of child-bearing potential must be using an adequate and        reliable method of contraception (ie, barrier with additional        spermicidal foam or jelly, intra-uterine device, hormonal        contraception). Females who are postmenopausal must have been        postmenopausal ≧1 year and have elevated serum FSH.

Exclusion Criteria

The following criteria excluded potential subjects from the study.

-   -   Females who are pregnant (positive beta human chorionic        gonadotropin test) or lactating.    -   Current or recent (within 5 years) history of drug or alcohol        abuse.    -   History or any current conditions that might interfere with drug        absorption, distribution, metabolism or excretion.    -   Use of an opioid-containing medication in the past 30 days        preceding the initial dose of study drug in this study.    -   History of known sensitivity to hydrocodone, naltrexone, or        related compounds.    -   Any history of frequent nausea or emesis regardless of etiology.    -   Any history of seizures or head trauma with sequelae.    -   Participation in a clinical drug study during the 30 days        preceding the initial dose of study drug in this study.    -   Any significant illness during the 30 days preceding the initial        dose of study drug in this study.    -   Use of any medication including thyroid hormonal therapy        (hormonal contraception and hormonal replacement therapy in the        form of estrogen with or without progestin is allowed),        vitamins, herbal and/or mineral supplements during the 7 days        preceding the initial dose of study drug.    -   Any personal or family history of prolonged QT interval or        disorders of cardiac rhythm.    -   Abnormal cardiac conditions including any of the following:        -   QTc interval ≧450 msec (calculated using Fridericia's            correction) at screening        -   QTc interval ≧480 msec (calculated using Fridericia's            correction) during the treatment period.    -   Refusal to abstain from food 10 hours preceding and 4 hours        following study drug administration and to abstain from caffeine        or xanthine containing beverages entirely during each        confinement.    -   Refusal to abstain from consumption of alcoholic beverages 48        hours prior to initial study drug administration (day 1) and any        time through the end of study visit.    -   Blood or blood products donated within 30 days prior to initial        study drug administration or anytime through the end of study        visit, except as required by this protocol.    -   History of smoking or use of nicotine products within 45 days of        initial study drug administration or a positive urine cotinine        test.    -   Positive results of urine drug screen or alcohol screen.    -   Positive results of HBsAg, anti-HCV.    -   Positive naloxone HCl challenge test.    -   Presence of Gilbert's Syndrome, or any known hepatobiliary        abnormalities.    -   The investigator believes the subject to be unsuitable for        reason(s) not specifically stated in the exclusion criteria.

Subjects meeting all the inclusion criteria and none of the exclusioncriteria were randomized into the study.

Each subject was assigned a unique subject number at screening.Assignment of subject numbers was in ascending order and no numbers wereomitted. Subject numbers were used on all study documentation.

Check-in Procedures

On Day −1 of Period 1 only, subjects were admitted to the study unit andreceived a Naloxone HCl challenge test. The results of the test had tobe negative for subjects to continue in the study. Vital signs and SPO₂were measured prior to and following the Naloxone HCl.

The following procedures were also performed for all subjects atCheck-in for each period:

-   -   Verification of inclusion/exclusion criteria, including        verification of willingness to comply with caffeine and xanthine        restriction criteria.    -   Vital signs (after being seated for approximately 5 minutes) and        SpO2.    -   HDYF (How do you feel) ? Inquiry was performed at the same time        vital signs were measured.    -   Clinical laboratory evaluations (day −1, period 1 only)        including biochemistry (fasting for at least 4 hours),        hematology and urinalysis) were collected after vital signs and        SpO₂ were measured.    -   Screen for alcohol (via urine or blood alcohol or breathalyzer        test), cotinine, and selected drugs of abuse (via urine        testing).    -   Urine pregnancy test (for all female subjects).    -   Concomitant medication monitoring and recording.    -   AE monitoring and recording.

For subjects to continue their participation in the study, the resultsof the drug screen (including alcohol and cotinine) had to be availableand negative prior to dosing. In addition, continued compliance withconcomitant medication and other restrictions were verified at Check-inand throughout the study in the appropriate source documentation.

Treatment Period Procedures

Treatments to be studied were predetermined for each Iteration. Withinan Iteration, as data became available, treatments were dropped betweencohorts. Dropped treatments were replaced with repeats of remainingtreatments.

-   -   Prior to the first dose in period 1, subjects were randomized to        a treatment sequence.    -   Subjects received naltrexone HCl tablets (50 mg) with 240 mL of        water at −12 h prior to study drug dosing.    -   Subjects were administered the study drug with 240 mL of water        as following a 10-hour overnight fast. Subjects continued        fasting from food for 4 hours following dosing.        -   Subjects were standing or in an upright sitting position            while receiving their dose of study drug.        -   Fasting was not required for nondosing study days.    -   Subjects received naltrexone HCl 50-mg tablets with 240 mL of        water at −12, 0, 12, 24, and 36 hours relative to each study        drug dosing.    -   For subjects receiving hydrocodone doses of 60 mg or more, SpO₂        was monitored continuously beginning prior to dosing and        continuing through 24 hours post-dose.    -   Vital signs (after being seated for approximately 5 minutes) and        SpO₂, were obtained pre-dose and at hour 1, 2.5, 4, 6, 8, 12,        24, 36, 48, and 72 hour post dose for each period.    -   HDYF (How do you feel) ? Inquiry was performed at the same time        vital signs were measured.    -   12-lead ECGs were performed for each subject pre-dose and        approximately 12, 24 and 48 hours post-dose.    -   Blood samples for determining hydrocodone plasma concentrations        were obtained for each subject at pre-dose and at 0.5, 1, 2.5,        4, 6, 8, 10, 12, 14, 16, 18, 24, 36, 48, and 72 hours post-dose        for each period.    -   Subjects were confined to the unit from check-in to the unit on        the day before dosing until the time that their 72 h procedures        were completed.    -   During the study, AEs and concomitant medications were recorded.

In addition, the subjects were informed that it is very important toreport any/all episodes of emesis to the study staff immediately andthat this information is crucial to the proper conduct and outcome ofthe trial. The subjects were informed that they would not be penalizedin any way due to reporting cases of emesis. The study staff wasinstructed to carefully document any/all cases of emesis.

Study Completion Procedures

The following procedures were performed at the study site for allsubjects at end-of-study (study completion), 7 to 10 days afterreceiving their last dose of study drug or upon early discontinuationfrom the study.

-   -   Concomitant medication evaluation.    -   Vital signs (after being seated for approximately 5 minutes) and        SpO₂.    -   HDYF? Inquiry was performed at the same time vital signs are        measured.    -   Physical examination.    -   12-Lead ECG.    -   Clinical laboratory evaluations (including biochemistry [fasted        at least 4 hours], hematology, and urinalysis).    -   AE evaluations.    -   Serum pregnancy test (for female subjects only).

The draft results are set forth in FIG. 7 and Table 17 below:

TABLE 17 Summary of Draft Plasma Hydrocodone Pharmacokinetic ParametersParameter HYD 20 mg HYD 40 mg HYD 60 mg HYD 80 mg HYD 120 mg (Unit)Statistic (N = 29) (N = 30) (N = 28) (N = 30) (N = 29) AUCt MEAN 281 6181004 1298 1759 (ng * h/mL) SD 127 255 292 373 671 MIN 30 85 580 559 303MAX 591 1200 1724 2501 3324 AUCinf Mean 284 622 1009 1304 1768 (ng *h/mL) SD 128 256 294 375 674 Min 31 86 583 564 305 Max 595 1213 17422514 3347 Cmax Mean 15 34 54 69 110 (ng/mL) SD 5.5 12 15 17 44 Min 3.57.6 33 40 28 Max 26 54 83 109 199 Tmax (h) Mean 15 16 16 15 15 SD 4.54.5 4.7 2.6 4.4 Min 6 6 10 10 6 Median 16 16 14 16 14 Max 24 24 30 24 30

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

1-129. (canceled)
 130. A method of preparing a solid controlled releasedosage form comprising: preparing a core comprising a first portion ofan opioid analgesic dispersed in a first matrix material; and encasingthe core with a shell comprising a second portion of the opioidanalgesic dispersed in a second matrix material; wherein the amount ofopioid analgesic released from the dosage form is proportional within20% to elapsed time from 8 to 24 hours, as measured by an in-vitrodissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) at 37° C.
 131. A method of preparinga solid controlled release dosage form comprising: preparing a corecomprising a first portion of an opioid analgesic dispersed in a firstmatrix material comprising polyethylene oxide; and encasing the core ina shell comprising a second portion of the opioid analgesic dispersed ina second matrix material comprising polyethylene oxide.
 132. A method ofpreparing a solid controlled release dosage form comprising: preparing acompressed core comprising a first portion of an opioid analgesicdispersed in a first matrix material comprising polyethylene oxide; andencasing the core by compression coating a second portion of the opioidanalgesic dispersed in a second matrix material comprising polyethyleneoxide over the core.
 133. A method of preparing a solid controlledrelease dosage form comprising: preparing a core comprising a firstportion of an opioid analgesic dispersed in a first matrix material; andencasing the core in a shell comprising a second portion of the opioidanalgesic dispersed in a second matrix material over the core; whereinthe amount of opioid analgesic released from the dosage form at 2 hoursis less than about 25%; the amount of opioid analgesic released from thedosage form at 4 hours is from about 10% to about 30%; the amount ofopioid analgesic released from the dosage form at 8 hours is from about20% to about 60%; the amount of opioid analgesic released from thedosage form at 12 hours is from about 40% to about 90%; the amount ofopioid analgesic released from the dosage form at 18 hours is greaterthan about 70%; and as measured by an in-vitro dissolution in a USPApparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) at 37° C. 134-136. (canceled)
 137. The method ofpreparing a solid controlled release dosage form of claim 133, whereinboth the first matrix material and the second matrix material comprisepolyethylene oxide.
 138. The method of preparing a solid controlledrelease dosage form of claim 137, wherein the polyethylene oxide in thesecond matrix material has a higher viscosity than the polyethyleneoxide in the first matrix material.
 139. The method of preparing a solidcontrolled release dosage form of claim 133, wherein the first matrixmaterial comprises polyethylene oxide having an average molecular weightfrom about 300,000 to about 10,000,000.
 140. The method of preparing asolid controlled release dosage form of claim 139, wherein the secondmatrix material comprises polyethylene oxide having an average molecularweight from about 1,000,000 to about 10,000,000.
 141. The method ofpreparing a solid controlled release dosage form of claim 140, whereinthe weight ratio of the core to the shell is from about 1:0.5 to about1:5.
 142. The method of preparing a solid controlled release dosage formof claim 137, wherein the weight ratio of the first portion of opioidanalgesic to polyethylene oxide in the first matrix material is fromabout 1:0.5 to about 1:100.
 143. The a method of preparing a solidcontrolled release dosage form of claim 133, wherein the opioidanalgesic in the first portion is the same as the opioid analgesic inthe second portion.
 144. The method of preparing a solid controlledrelease dosage form of claim 133, wherein the opioid analgesic in thefirst portion is different than the opioid analgesic in the secondportion.
 145. The method of preparing a solid controlled release dosageform of claim 133, wherein the ratio of opioid analgesic in the core tothe ratio of opioid analgesic in the shell is from about 1:1 to about10:1.
 146. The method of preparing a solid controlled release dosageform of claim 133, wherein the opioid analgesic is selected from thegroup consisting of alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propoxyphene, sufentanil, tilidine, tramadol,pharmaceutically acceptable salts thereof, hydrates thereof, solvatesthereof, and mixtures thereof.
 147. The method of preparing a solidcontrolled release dosage form of claim 146, wherein the opioidanalgesic is selected from the group consisting of codeine, hydrocodone,hydromorphone, morphine, oxycodone, oxymorphone, tramadol,pharmaceutically acceptable salts thereof, hydrates thereof, solvatesthereof, and mixtures thereof.
 148. The method of preparing a solidcontrolled release dosage form of claim 147, wherein the opioidanalgesic is selected from the group consisting of hydrocodone,pharmaceutically acceptable salts thereof, hydrates thereof, solvatesthereof, and mixtures thereof.
 149. The method of preparing a solidcontrolled release dosage form of claim 148, wherein the opioidanalgesic is hydrocodone bitartrate.
 150. The method of preparing asolid controlled release dosage form of claim 149, wherein total amountof hydrocodone bitartrate in the dosage form is from about 0.5 mg toabout 1250 mg.
 151. The method of preparing a solid controlled releasedosage form of claim 137, wherein the dosage form is cured at atemperature of at least the softening point of the polyethylene oxidefor at least 1 minute.
 152. The method of preparing a solid controlledrelease dosage form of claim 151, wherein the dosage form is cured at atemperature of at least about 60° C.
 153. The method of preparing asolid controlled release dosage form of claim 148, that provides aC₂₄/C_(max) ratio of hydrocodone of about 0.55 to about 1.0 afteradministration.
 154. The method of preparing a solid controlled releasedosage form of claim 148, that provides a T_(max) (h) of hydrocodonefrom about 4 to about 20 hours after administration.